Restoration of Pregnancy Function Using a GT/PCL Biofilm in a Rabbit Model of Uterine Injury.

Biomaterial scaffolds have been used successfully to promote the regenerative repair of small endometrial lesions in small rodents, providing partial restoration of gestational function. The use of rabbits in this study allowed us to investigate a larger endometrial tissue defect and myometrial injury model. A gelatin/polycaprolactone (GT/PCL) gradient-layer biofilm was sutured at the defect to guide the reconstruction of the original tissue structure. Twenty-eight days postimplantation, the uterine cavity had been restored to its original morphology, endometrial growth was accompanied by the formation of glands and blood vessels, and the fragmented myofibers of the uterine smooth muscle had begun to resemble the normal structure of the lagomorph uterine cavity, arranging in a circular luminal pattern and a longitudinal serosal pattern. In addition, the repair site supported both embryonic implantation into the placenta and normal embryonic development. Four-dimensional label-free proteomic analysis identified the cell adhesion molecules, phagosome, ferroptosis, rap1 signaling pathways, hematopoietic cell lineage, complement and coagulation cascades, tricarboxylic acid cycle, carbon metabolism, and hypoxia inducible factor (HIF)-1 signaling pathways as important in the endogenous repair process of uterine tissue injury, and acetylation of protein modification sites upregulated these signaling pathways.

Taiyi: a bilingual fine-tuned large language model for diverse biomedical tasks.

OBJECTIVE: Most existing fine-tuned biomedical large language models (LLMs) focus on enhancing performance in monolingual biomedical question answering and conversation tasks. To investigate the effectiveness of the fine-tuned LLMs on diverse biomedical natural language processing (NLP) tasks in different languages, we present Taiyi, a bilingual fine-tuned LLM for diverse biomedical NLP tasks. MATERIALS AND METHODS: We first curated a comprehensive collection of 140 existing biomedical text mining datasets (102 English and 38 Chinese datasets) across over 10 task types. Subsequently, these corpora were converted to the instruction data used to fine-tune the general LLM. During the supervised fine-tuning phase, a 2-stage strategy is proposed to optimize the model performance across various tasks. RESULTS: Experimental results on 13 test sets, which include named entity recognition, relation extraction, text classification, and question answering tasks, demonstrate that Taiyi achieves superior performance compared to general LLMs. The case study involving additional biomedical NLP tasks further shows Taiyi's considerable potential for bilingual biomedical multitasking. CONCLUSION: Leveraging rich high-quality biomedical corpora and developing effective fine-tuning strategies can significantly improve the performance of LLMs within the biomedical domain. Taiyi shows the bilingual multitasking capability through supervised fine-tuning. However, those tasks such as information extraction that are not generation tasks in nature remain challenging for LLM-based generative approaches, and they still underperform the conventional discriminative approaches using smaller language models.

Role of Caveolae family-related proteins in the development of breast cancer.

Breast cancer has become the most significant malignant tumor threatening women's lives. Caveolae are concave pits formed by invagination of the plasma membrane that participate in many biological functions of the cell membrane, such as endocytosis, cell membrane assembly, and signal transduction. In recent years, Caveolae family-related proteins have been found to be closely related to the occurrence and development of breast cancer. The proteins associated with the Caveolae family-related include Caveolin (Cav) and Cavins. The Cav proteins include Cav-1, Cav-2 and Cav-3, among which Cav-1 has attracted the most attention as a tumor suppressor and promoting factor affecting the proliferation, apoptosis, migration, invasion and metastasis of breast cancer cells. Cav-2 also has dual functions of inhibiting and promoting cancer and can be expressed in combination with Cav-1 or play a regulatory role alone. Cav-3 has been less studied in breast cancer, and the loss of its expression can form an antitumor microenvironment. Cavins include Cavin-1, Cavin-2, Cavin-3 and Cavin-4. Cavin-1 inhibits Cav-1-induced cell membrane tubule formation, and its specific role in breast cancer remains controversial. Cavin-2 acts as a breast cancer suppressor, inhibiting breast cancer progression by blocking the transforming growth factor (TGF-ß) signaling pathway. Cavin-3 plays an anticancer role in breast cancer, but its specific mechanism of action is still unclear. The relationship between Cavin-4 and breast cancer is unclear. In this paper, the role of Caveolae family-related proteins in the occurrence and development of breast cancer and their related mechanisms are discussed in detail to provide evidence supporting the further study of Caveolae family-related proteins as potential targets for the diagnosis and treatment of breast cancer.

Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions.

Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that androgen receptor (AR) forms condensates through multivalent interactions mediated by its N-terminal intrinsically disordered region (IDR) to orchestrate enhancer assembly in response to androgen signaling. AR IDR can be substituted by IDRs from selective proteins for AR condensation capacity and its function on enhancers. Expansion of the poly(Q) track within AR IDR results in a higher AR condensation propensity as measured by multiple methods, including live-cell single-molecule microscopy. Either weakening or strengthening AR condensation propensity impairs its heterotypic multivalent interactions with other enhancer components and diminishes its transcriptional activity. Our work reveals the requirement of an optimal level of AR condensation in mediating enhancer assembly and suggests that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies.

The relationship between the Hippo signaling pathway and bone metastasis of breast cancer.

Bone is the most common site of metastasis from breast cancer, which is the most prevalent cancer affecting women globally. Bone metastasis from breast cancer severely affects the quality of life of patients and increases mortality. The molecular mechanisms of metastasis, colonization, and proliferation of breast cancer cells in bone are complex and involve the interaction between breast cancer cells and the bone microenvironment. However, the precise mechanism is not clear at present. In recent years, the Hippo signaling pathway has attracted much attention due to its important role in regulating the expression of major effector molecules during tumor development. In particular, studies have found that the mutation and aberrant expression of the core components of the Hippo signaling pathway affect breast cancer cell migration and invasion, indicating that this pathway plays a role in bone metastasis, although the molecular mechanism of this pathway in breast cancer metastasis has not been fully elucidated. In this review, we discuss the function of the Hippo signaling pathway, introducing its role in breast cancer metastasis, especially bone metastasis of breast cancer, so as to lay a solid theoretical foundation for further research and for the development of effective targeted therapeutic agents.

Mutant NPM1 Hijacks Transcriptional Hubs to Maintain Pathogenic Gene Programs in Acute Myeloid Leukemia.

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes-HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention. SIGNIFICANCE: NPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517.

Recomposition and storage of sunlight with intelligent phosphors for enhanced photosynthesis.

This work presents a smart solar energy regulation strategy using photon tunable long persistent phosphors as solar energy harvesting antennas to enhance overall sunlight utilization by photosynthetic organisms in multiple modes.

Near-Infrared Light Brightens Bacterial Disinfection: Recent Progress and Perspectives.

Bacterial infection is a universal threat to public health, which not only causes many serious diseases but also exacerbates the condition of the patients of cancer, pandemic diseases, e.g., COVID-19, and so on. Antibiotic therapy has been used to be an effective way for common bacterial disinfection. However, due to the misuse and abuse of antibiotics, more and more antibiotic-resistant bacteria have emerged as fatal threats to human beings. At present, more than 700,000 patients die every year with bacterial infections because of the lack of effective treatment. It is frustrating that the pace of development of antibiotics lags far behind that of bacterial resistance, with an estimation of 10 million deaths per year from bacterial infections after 2050. Facing such a rigorous challenge, approaches for bacterial disinfection are urgently demanded. The recently developed near-infrared (NIR) light-irradiation-based bacterial disinfection is highly promising to shatter bacterial resistance by employing NIR light-responsive materials as mediums to generate antibacterial factors such as heat, reactive oxygen species (ROS), and so on. This treatment approach is proved to be a potent candidate to accurately realize spatiotemporal control, while effectively eradicating multidrug-resistant bacteria and inhibiting antibiotic resistance. Herein, we summarize the latest progress of NIR light-based bacterial disinfection. Ultimately, current challenges and perspectives in this field are discussed.

Luminescent molecules towards precise cellular event regulation.

A unique lanthanide complex which responds to near-infrared (NIR) stimulation was developed for remote regulation of cellular events. This molecule can be localized specifically on the cell surface. Upon NIR stimulation, strong emission of the complex can successfully modulate the activities of light-gated membrane channels and regulate the ion flux in vivo.

Metallic Nanoparticle-Enabled Sensing of a Drug-of-Abuse: An Attempt at Forensic Application.

γ-Hydroxybutyric acid (GHB) functions as a depressant on the central nerve system and serves as a pharmaceutical agent in the treatment of narcolepsy and alcohol withdraw. In recent years, GHB has been misused as a recreational drug due to its ability to induce euphoric feelings. Moreover, it has gained increasing attention as a popular drug of abuse that is frequently related to drug-facilitated sexual assaults. At the moment, detection methods based on chromatography exhibit extraordinary sensitivity for GHB sensing. However, such techniques require complicated sample treatment prior to analysis. Optical sensors provide an alternative approach for rapid and simple analysis of GHB samples. Unfortunately, currently reported probes are mostly based on hydrogen bonding to recognize GHB, and this raises concerns about, for example, the lack of specificity. In this work, we report a bioinspired strategy for selective sensing of GHB. The method is based on specific enzyme recognition to allow highly selective detection of GHB with minimum interference, even in a complex sample matrix (e. g., simulated urine). In addition, the result can be obtained by either quantitative spectroscopy analysis or colorimetric change observed by the naked-eye, thus demonstrating its potential application in drug screening and forensic analysis.

Extraspecific Manifestation of Nanoheater's Position Effect on Distinctive Cellular Photothermal Responses.

Subcellular localization of nanoparticles plays critical roles in precision medicine that can facilitate an in-depth understanding of disease etiology and achieve accurate theranostic regulation via responding to the aiding stimuli. The photothermal effect is an extensively employed strategy that converts light into heat stimulation to induce localized disease ablation. Despite diverse manipulations that have been investigated in photothermal nanotheranostics, influences of nanoheaters' subcellular distribution and their molecular mechanism on cellular heat response remain elusive. Herein, we disclose the biological basis of distinguishable thermal effects at subcellular resolution by localizing photothermal upconversion nanoparticles into specific locations of cell compartments. Upon 808 nm light excitation, the lysosomal cellular uptake initialized by poly(ethylenimine)-modified nanoheaters promoted mitochondria apoptosis through the activation of Bid protein, whereas the cell surface nanoheaters anchored via metabolic glycol biosynthesis triggered necrosis by direct perturbation of the membrane structure. Intriguingly, these two different thermolyses revealed similar levels of heat shock protein expression in live cells. This study stipulates insights underlying the different subcellular positions of nanoparticles for the selective thermal response, which provides valuable perspectives on optimal precision nanomedicine.

dl-3-n-butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion.

AIMS: Effects of dl-3-n-butylphthalide (NBP) on white matter damage and cognitive impairment in vascular cognitive impairment (VCI) have not been well studied. This study aimed to investigate the effects of NBP treatment on chronic cerebral hypoperfusion-induced white matter lesions and cognitive dysfunction in mice. METHODS: Mice were subjected to bilateral common carotid artery stenosis (BCAS) for over 30 days. The cerebral blood flow was detected using a laser Doppler flowmetry. Cognitive functions were assessed by several behavioral tests. We also evaluated the effects of NBP on the blood-brain barrier (BBB) disruption and reactive astrogliosis, using Evans Blue extravasation, Western blot, CBA, and immunofluorescence in BCAS mice and cultured astrocytes. RESULTS: The results indicated that NBP treatment attenuated spatial memory dysfunction while promoted cerebral perfusion and white matter integrity in BCAS mice. Moreover, NBP treatment prevented BBB leakage and damage of endothelial cells, as well as disruption of endothelial tight junctions. Furthermore, NBP administration effectively decreased the number of activated astrocytes and pro-inflammatory cytokines, as well as the production of MMPs, in BCAS-induced mice and LPS-stimulated astrocytes. CONCLUSION: Our results indicated that NBP represents a promising therapy for chronic cerebral hypoperfusion-induced white matter damage and cognitive impairment.