Advanced Science最新文献

Navigating complex extracellular environments requires extensive deformation of cells and their nuclei. Most in vitro systems used to study nuclear deformations impose whole-cell confinement that mimics the physical crowding experienced by cells during 3D migration through tissues. Such systems, however, do not reproduce the types of nuclear deformations expected to occur in cells that line tissues such as endothelial or epithelial cells whose physical confinement stems principally from the topography of their underlying basement membrane. Here, it is shown that endothelial cells and myoblasts cultured on microgroove substrates that mimic the anisotropic topography of the basement membrane exhibit large-scale 3D nuclear deformations, with partial to complete nuclear penetration into the microgrooves. These deformations do not lead to significant DNA damage and are dynamic with nuclei cyclically entering and exiting the microgrooves. Atomic force microscopy measurements show that these deformation cycles are accompanied by transient changes in perinuclear stiffness. Interestingly, nuclear penetration into the grooves is driven principally by cell-substrate adhesion stresses, with a limited need for cytoskeleton-associated forces. Finally, it is demonstrated that myoblasts from laminopathy patients exhibit abnormal nuclear deformations on microgrooves, raising the possibility of using microgroove substrates as a novel functional diagnostic platform for pathologies that involve abnormal nuclear mechanics.

The growing demand for environmentally friendly semiconductors that can be tailored and developed easily is compelling researchers and technologists to design inherently bio-compatible, self-assembling nanostructures with tunable semiconducting characteristics. Peptide-based bioinspired materials exhibit a variety of supramolecular morphologies and have the potential to function as organic semiconductors. Such biologically or naturally derived peptides with intrinsic semiconducting characteristics create new opportunities for sustainable biomolecule-based optoelectronics devices. Affably, halide perovskite nanocrystals are emerging as potentially attractive nano-electronic analogs, in this vein creating synergies and probing peptide-perovskite-based bio-electronics are of paramount interest. The physical properties and inherent aromatic short-peptide assemblies that can stabilize, and passivate the defects at surfaces assist in improving the charge transport in halide perovskite devices. This review sheds light on how these peptide-perovskite nano-assemblies can be developed for optical sensing, optoelectronics, and imaging for biomedical and healthcare applications. The charge transfer mechanism in peptides along with as an outlook the electron transfer mechanism between perovskite and short peptide chains, which is paramount to facilitate their entry into molecular electronics is discussed. Future aspects, prevailing challenges, and research directions in the field of perovskite-peptides are also presented.

Lithium metal batteries are considered the holy grail for next-generation high-energy systems. However, lithium anode faces poor reversibility, unsatisfying cyclability and rate capability due to its uncontrollable plating/stripping behavior. While galvanostatic conditions are extensively studied, the behavior under more realistic application scenarios with variable inputs are less explored. Here, an in situ imaging platform using in-plane microdevice configurations is developed to effectively investigate Li plating/stripping behavior under dynamic conditions. This platform offers high detectivity for analyzing the nuclei size, density, distribution, and growth location, rate, and mode. It is for the first time revealed that nuclei density and growth locations remain constant and are solely determined by the initial nucleation overpotentials during dynamic plating. A transition in growth modes from uniform granular growth to tip-induced dendrite growth, and finally to directional growth among the dendrites is also observed. Guided by these findings, a dynamic plating protocol is proposed, which can greatly improve the Li reversibility and cycling stability. This work not only provides a novel approach to visualize the evolution of key nucleation and growth parameters, especially under variable inputs, but also offers valuable guidance for the future industrialization of metal batteries and the rational design of charging facilities.

Repairing large bone defects remains a significant clinical challenge. Stem cell is of great importance in bone regeneration, and periosteum is rich in periosteal stem cell, which has a great influence on repairing bone defects. Bioengineered periosteum with excellent biocompatibility and stem cell homing capabilities to promote bone regeneration is of great clinical significance. The E7 peptide (EPLQLKM), which exhibits a specific affinity for mesenchymal stem cells (MSCs), is beneficial for modulating cellular functions. In this study, a unique microporous structured carboxymethyl chitosan/sodium alginate membrane with a proper mass ratio is developed by the addition of Poloxam 407 （P407）, which is then functionalized with the E7 affinitive peptide. This membrane, characterized by its microporous structure and E7 peptide functionalization (CSSA/P/E), not only demonstrated favorable mechanical properties, enhanced hydrophilicity, satisfactory biodegradation profile, and excellent biocompatibility, but also synergistically enhanced MSCs recruitment. It is found to promote the proliferation, spreading, and osteogenic differentiation of MSCs in vitro and to accelerate early periosteal regeneration, bone matrix deposition, and vascularization in vivo, leading to effective regeneration of critical-sized bone defects. Overall, this study presents a robust, cell and growth factor-free strategy for bioengineering periosteum, offering a potential solution for the challenging large size bone defects.

Usher syndrome type 1C (USH1C) is a genetic disorder caused by mutations in the USH1C gene, which encodes harmonin, a key component of the mechanoelectrical transduction complex in auditory and vestibular hair cells. USH1C leads to deafness and vestibular dysfunction in humans. An Ush1c knockout (KO) mouse model displaying these characteristic deficits is generated in our laboratory. To examine gene replacement therapy (GT) in this model, a synthetic adeno-associated viral vector, Anc80L65, driving harmonin expression is administered, to the inner ears of Ush1c KO mice at postnatal day 2 (P2). Remarkably, this single treatment significantly improved auditory brainstem response (ABR) thresholds and balance motor function at 1 month post-injection, with these effects persisting for up to 10 months. At 12 months post-treatment, the vestibular function is assessed using the vestibular-ocular reflexes (VOR) and single vestibular afferent recordings. The GT treatment significantly restored both the canal and otolith VORs and increased vestibular afferent spontaneous firing rates and responses to head rotation and translation. These findings provide the first evidence of long-lasting restoration of both the auditory and vestibular functions by GT in a novel mouse model of Usher syndrome, highlighting the potential of GT for treating deficits associated with USH1C.

METTL3, a key enzyme in N6-methyladenosine (m6A) modification, plays a crucial role in the progression of renal fibrosis, particularly in chronic active renal allograft rejection (CAR). This study explored the mechanisms by which METTL3 promotes renal allograft fibrosis, focusing on its role in the macrophage-to-myofibroblast transition (MMT). Using a comprehensive experimental approach, including TGF-β1-induced MMT cell models, METTL3 conditional knockout (METTL3 KO) mice, and renal biopsy samples from patients with CAR, the study investigates the involvement of METTL3/Smad3 axis in driving MMT and renal fibrosis during the episodes of CAR. We found that elevated m6A modification and METTL3 levels strongly correlated with enhanced MMT and increased fibrotic severity. METTL3 knockout (METTL3 KO) significantly increased the m6A modification of Smad3, decreased Smad3 expression, and inhibited M2-driven MMT. Smad3 knockdown with siRNA (siSmad3) further inhibited M2-driven MMT, while Smad3 overexpression rescued the inhibitory effects of METTL3 silencing, restoring M2-driven MMT and fibrotic tissue damage. Additionally, the METTL3 inhibitor STM2457 effectively reversed M2-driven MMT and alleviated fibrotic tissue damage in CAR. These findings highlight that METTL3 enhances M2-driven MMT in renal fibrosis during CAR by promoting the TGF-β1/Smad3 axis, suggesting that METTL3 is a promising therapeutic target for mitigating renal fibrosis in CAR.

Polycyclic multiple resonance (MR) molecules reveal narrowband emission, making them very promising emitters for high color purity display. Nevertheless, they still have challenges such as aggregation-induced emission quenching and spectral broadening. Overcoming these obstacles requires an in-depth understanding of the correlations among the alterations in their geometries, packing structures, and molecular vibrations and their corresponding changes in their photoluminescence (PL) properties. Herein, it is demonstrated that high-pressure infrared, UV-visible absorption, and fluorescence spectroscopies can be combined with computational results to elucidate the influence of the subtle structural variations on the exciton‒vibration couplings and their PL properties. An ortho-carborane-decorated MR emitter (BNC) is a piezochromic molecule and exhibits emission enhancement under high pressure. A thorough analysis of the in situ experimental measurements and calculated results reveals that the pressure-induced changes in the exciton binding energy and exciton‒vibration couplings are responsible for the unusual piezochromism. This research provides insights into the structure‒fluorescence relationship and potential for high-pressure techniques to optimize MR materials for advanced organic light-emitting diodes (OLEDs) applications.

The efficient isolation and molecular analysis of circulating tumor cells (CTCs) from whole blood at single-cell level are crucial for understanding tumor metastasis and developing personalized treatments. The viability of isolated cells is the key prerequisite for the downstream molecular analysis, especially for RNA sequencing. This study develops a laser-induced forward transfer -assisted microfiltration system (LIFT-AMFS) for high-viability CTC enrichment and retrieval from whole blood. The LIFT-compatible double-stepped microfilter (DSMF), central to this system, comprises two micropore layers: the lower layer's smaller micropores facilitate size-based cell separation, and the upper layer's larger micropores enable liquid encapsulating captured cells. By optimizing the design of the DSMFs, the system has a capture efficiency of 88% at the processing throughput of up to 15.0 mL min^-1 during the microfilter-based size screening stage, with a single-cell yield of over 95% during the retrieval stage. The retrieved single cells, with high viability, are qualified for ex vivo culture and direct RNA sequencing. The cDNA yield from isolated CTCs surpassed 4.5 ng, sufficient for library construction. All single-cell sequencing data exhibited Q30 scores above 95.92%. The LIFT-AMFS shows promise in cellular and biomedical research.

Stem cell implantation holds promise for enhancing bone repair, but risks of pathogen transmission and malignant cell transformation should not be ignored. Compared to stem cell implantation, recruitment of endogenous stem cells to injured sites is more critical for in situ bone regeneration. In this study, based on the acidic microenvironment of bone injury, an HG-AA_1:1-SDF-1α composite hydrogel with a dual-control intelligent switch function is developed by incorporating stromal cell-derived factor (SDF-1α), arginine carbon dots (Arg-CDs), and calcium ions (Ca²⁺) into the oxidized hyaluronic acid/gelatin methacryloyl (HG) hydrogel. The acidic microenvironment triggers the first switch (Schiff base bond is broken between HG-AA_1:1 and SDF-1α) of HG-AA_1:1-SDF-1α composite hydrogel to continuously release SDF-1α. Compared to the neutral (pH 7.4) media, the cumulative release of SDF-1α in acidic (pH 5.5) media is ≈2.5 times higher, which enhances the migration and recruitment of endogenous mesenchymal stem cells (MSCs). The recruited MSCs immediately initiate the second switch and metabolize Arg-CDs into the bioactive nitric oxide (NO) in the presence of Ca²⁺, activating NO/cyclic guanosine monophosphate (cGMP) signaling pathway to promote angiogenesis. Therefore, the engineered HG-AA_1:1-SDF-1α composite hydrogel shows promising potential to achieve "coupling osteogenesis and angiogenesis" for bone regeneration.

Triple-negative breast cancer (TNBC) in obese patients remains challenging. Recent studies have linked obesity to an increased risk of TNBC and malignancies. Through multiomic analysis and experimental validation, a dysfunctional Eukaryotic Translation Initiation Factor 3 Subunit H (EIF3H)/Yes-associated protein (YAP) proteolytic axis is identified as a pivotal junction mediating the interplay between cancer-associated adipocytes and the response to anti-cancer drugs in TNBC. Mechanistically, cancer-associated adipocytes drive metabolic reprogramming resulting in an upregulated hexosamine biosynthetic pathway (HBP). This aberrant upregulation of HBP promotes YAP O-GlcNAcylation and the subsequent recruitment of EIF3H deubiquitinase, which stabilizes YAP, thus promoting tumor growth and chemotherapy resistance. It is found that Retatrutide, an anti-obesity agent, inhibits HBP and YAP O-GlcNAcylation leading to increased YAP degradation through the deprivation of EIF3H-mediated deubiquitylation of YAP. In preclinical models of obese TNBC, Retatrutide downregulates HBP, decreases YAP protein levels, and consequently decreases tumor size and enhances chemotherapy efficacy. This effect is particularly pronounced in obese mice bearing TNBC tumors. Overall, these findings reveal a critical interplay between adipocyte-mediated metabolic reprogramming and EIF3H-mediated YAP proteolytic control, offering promising therapeutic strategies to mitigate the adverse effects of obesity on TNBC progression.