Advanced Science最新文献

Excessive fat accumulation and chronic inflammation are two typical characteristics of obesity. AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, is involved in adipogenesis, lipogenesis, and inflammation modulation in adipose tissue (AT). Thus, effective lipid reduction and anti-inflammation through AMPK regulation play vital roles in treating obesity. Herein, an anti-obesity nanosandwich is fabricated through attaching polymetformin (PolyMet) onto photothermal agent black phosphorus nanosheets (BP). PolyMet activates AMPK to inhibit adipogenesis, promote browning, and mitigate AT inflammation by decreasing macrophage infiltration, repolarizing macrophage phenotype, and downregulating pro-inflammatory cytokines. Additionally, BP induces lipolysis and apoptosis of adipocytes and macrophages through a photothermal effect. By further functionalization using hyaluronic acid (HA) and MMP2 substrate-linking P3 peptide-modified HA (P3-HA), an enhanced anti-obesity effect is obtained by dual-targeting of P3 and HA, and HA-mediated CD44 poly-clustering after MMP2 cleavage. Upon laser irradiation, the designed nanosandwich (P3-HA/PM@BP) effectively inhibits obesity development in obese mice, increases M2/M1 ratio in AT, reduces the serum levels of cholesterol/triglyceride and improves insulin sensitivity, exhibiting promising research potential to facilitate the clinical development of modern anti-obesity therapies.

Cancer Cells' Mastery of Their Environment

Cancer cells actively reshape their surroundings. By releasing sonic hedgehog, they stiffen the extracellular matrix, enlisting stromal cells as allies. This increased stiffness heightens actomyosin cytoskeleton tension, activating oncogenic transcription factors and driving invasive tumor growth. More details can be found in article number 2400063 by Jeongeun Hyun, Hae-Won Kim, and co-workers.

Conductivity-Dependent Neuronal Specification

In article number 2400586, Hae-Won Kim, Jung-Hwan Lee, and co-workers show that neural-tissue-like, low conductivity (0.02–0.1 S m–1) promotes neuronal differentiation via balanced calcium signaling and epigenetic changes, while supraphysiological, high conductivity (3.2 S m–1) causes apoptosis. This work reveals optimal conductivity's crucial role in neural interface design for tissue engineering and regenerative medicine.

Antimicrobial peptides (AMPs) are a promising solution for treating antibiotic-resistant pathogens. However, efficient generation of diverse AMPs without prior knowledge of peptide structures or sequence alignments remains a challenge. Here, ProT-Diff is introduced, a modularized deep generative approach that combines a pretrained protein language model with a diffusion model for the de novo generation of AMPs sequences. ProT-Diff generates thousands of AMPs with diverse lengths and structures within a few hours. After silico physicochemical screening, 45 peptides are selected for experimental validation. Forty-four peptides showed antimicrobial activity against both gram-positive or gram-negative bacteria. Among broad-spectrum peptides, AMP_2 exhibited potent antimicrobial activity, low hemolysis, and minimal cytotoxicity. An in vivo assessment demonstrated its effectiveness against a drug-resistant E. coli strain in acute peritonitis. This study not only introduces a viable and user-friendly strategy for de novo generation of antimicrobial peptides, but also provides potential antimicrobial drug candidates with excellent activity. It is believed that this study will facilitate the development of other peptide-based drug candidates in the future, as well as proteins with tailored characteristics.

Neuroendocrine regulation is essential for maintaining metabolic homeostasis. However, whether neuroendocrine pathway influence bone metabolism and skeletal senescence is unelucidated. Here, a central neuroendocrine circuit is identified that directly controls osteogenesis. Using virus based tracing, this study is identified that melanin concentrating hormone (MCH) expressing neurons in the lateral hypothalamus (LH) are connected to the bone. Chemogenetic activation of MCH neurons in the LH induces osteogenesis, whereas inhibiting these neurons reduces osteogenesis. Meanwhile, MCH is released into the circulation upon chemogenetic activation of these neurons. Single cell sequencing reveals that blocking MCH neurons in the LH diminishes osteogenic differentiation of bone marrow stromal cells (BMSCs) and induces senescence. Mechanistically, MCH promotes BMSC differentiation by activating MCHR1 via PKA signaling, and activating MCHR1 by MCH agonists attenuate skeletal senescence in mice. By elucidating a brain-bone connection that autonomously enhances osteogenesis, these findings uncover the neuroendocrinological mechanisms governing bone mass regulation and protect against skeletal senescence.

The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M^pro) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust M^pro inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar M^pro inhibitory potency (IC₅₀ = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC₅₀ = 0.078 µM, no cytotoxicity: CC₅₀ > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC₅₀ = 1.95 µM) and similar efficacy to ensitrelvir (EC₅₀ = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC₅₀ = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in M^pro (EC₅₀ = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 M^pro for clinical therapy.

High-risk human papillomavirus (HPV) screening is crucial for cervical cancer prevention. However, laboratory-based nucleic acid amplification tests (NAATs) require costly equipment, designated lab space, and skilled personnel. Additionally, cervical swabs collected by healthcare professionals can be inconvenient, uncomfortable, and reduce privacy, limiting broader application and patient compliance. A SlipChip-based Integrated Point-of-Care (SIPOC) system featuring an injection-molded SlipChip is presented with preloaded reagents for nucleic acid extraction and a portable four-channel real-time quantitative PCR instrument for detection. This system incorporates a self-sampling method that allows participants to collect their own vaginal swabs, with the β-Globin gene as a control. After testing 130 participants for HPV-16 and HPV-18, 97.7% of the self-collected samples are valid. Among valid samples, 25 tested positive for HPV-16 and 9 for HPV-18. Compared to Roche's standard HPV PCR test, the SIPOC system shows 100% positive predictive value (PPV) for both HPV-16 and HPV-18 and negative predictive values (NPVs) of 99.0% and 99.1%, respectively. This system is promising for HPV screening in resource-limited settings and adaptable for other point-of-care NAAT applications, including home testing.

Mitochondrial-nuclear communication plays a vital role in maintaining cellular homeostasis. MOTS-c, a short peptide derived from the 12S rRNA of mitochondrial DNA, has been suggested as a retrograde mitochondrial signal. Although recent clinical studies have suggested a possible link between MOTS-c and human cancer, the role of MOTS-c in tumorigenesis has yet to be investigated. Here, MOTS-c levels are found to be reduced in both serum and tumor tissues from ovarian cancer (OC) patients, which are associated with poor patients' prognosis. Exogenous MOTS-c inhibits the proliferation, migration and invasion of OC cells, and induces cell cycle arrest and apoptosis. Mechanistically, MOTS-c interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. In addition, USP7 was identified as a deubiquitinase of LARS1, and MOTS-c can attenuates USP7-mediated LARS1 deubiquitination by competing with USP7 for binding to LARS1. Besides, LARS1 was found to be increased and play an important oncogenic function in OC. More importantly, MOTS-c displays a marked anti-tumor effect on OC growth without systemic toxicity in vivo. In conclusion, this study reveals a crucial role of MOTS-c in OC and provides a possibility for MOTS-c as a therapeutic target for the treatment of this manlignacy.

The incorporation of defects and cocatalysts is known to be effective in improving photocatalytic activity, yet their coupled contribution to the photocatalytic hydrogen evolution process has not been well-explored. In this study, We demonstrate that the incorporation of S vacancies and NiSe can contribute to the improvement of charge separation efficiency via the formation of a strong electric field within the bulk ZnIn₂S₄ (ZIS) and on its surface. More importantly, We also demonstrate that the synergy of S vacancies and NiSe benefits the overall hydrogen evolution activity by facilitating the H₂O adsorption and dissociation process. This is particularly important for hydrogen evolution taking place under alkaline conditions where the proton concentration is low, allowing ZISv-NiSe (containing abundant S vacancies) to outperform ZIS-NiSe under alkaline conditions. In contrast, under acid conditions, since there are already sufficient amounts of protons available for reaction, the hydrogen evolution activity became governed by the hydrogen adsorption/desorption process rather than the H₂O dissociation process. This leads to ZIS-NiSe exhibiting higher activity than ZISv-NiSe due to its more favorable hydrogen adsorption energy. The findings thus provide insights into how defect and cocatalyst modification strategies can be tailor-made to improve hydrogen evolution activity under different pH conditions.

Facing the global challenge of water scarcity, solar-driven desalination is considered a sustainable technology for obtaining freshwater from seawater. However, issues such as uncontrolled salt crystallization and bacterial contamination limit its efficiency and practicality. This study proposes an innovative solar-driven evaporator designed to address these challenges using optimized shape design and advanced photothermal materials. Based on finite element analyses, cylindrical evaporators with a "Starburst Turbine" shape are designed and fabricated, achieving directional salt crystallization and a record-breaking water collection rate of 3.56 kg m^-2 h^-1 and an evaporation rate of 4.57 kg m^-2 h^-1 under one sun illumination. During continuous 60-h illumination tests, the evaporator maintained a stable evaporation rate, attributed to its excellent directional salt crystallization capability. Additionally, the evaporator demonstrates superior photodynamic antibacterial performance and photocatalytic degradation of organic pollutants. Under one sun illumination for 1 h, it achieves 100% sterilization of S. aureus and E. coli, and a 95.4% degradation of methylene blue (MB), demonstrating its potential to purify various wastewater types. These findings underscore the significant scientific and practical value of integrating antibacterial and photocatalytic functions into solar water purification materials, providing a sustainable solution to global water scarcity challenges and environmental protection.