Curcumin analogue AC17-loaded dissolvable microneedles activate FOXO3 and enhance localized drug delivery for oral squamous cell carcinoma treatment.

Curcumin, a polyphenol extracted from turmeric, is a potential alternative for the treatment of oral squamous cell carcinoma (OSCC) due to its remarkable anticancer activity and low systemic toxicity. To further enhance the anticancer activity and bioavailability of curcumin, we synthesized a curcumin analogue, AC17, by modifying the benzene ring and methylene group of curcumin. A soluble hyaluronic acid microneedle patch (AC17@HAMN) was developed to ensure accurate and safe delivery of AC17 to tumor tissues. The inhibitory effect of AC17 on OSCC cells was stronger than that of curcumin and some common analogues. Transcriptome sequencing showed that the target genes of AC17 were mainly concentrated in apoptosis, cell cycle and cell senescence pathways. Among them, AC17 induces cell cycle arrest and inhibits cell proliferation mainly by activating FOXO3 signaling. With good penetration and dissolution properties, microneedles can deliver AC17 directly to the tumor site and show good anti-tumor effect. Moreover, AC17@HAMN showed good biosafety. In summary, AC17@HAMN offers high efficiency, minimal invasiveness, and few adverse reactions. This microneedle patch holds great promise for potential clinical applications, especially for the treatment of OSCC.

The role of phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) in regulating the progression of oral squamous cell carcinoma.

OBJECTIVE: The aim of this study was to explore the role of the tumor suppressor phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) on oral squamous cell carcinoma (OSCC) and its molecular mechanism. DESIGN: Immunohistochemistry detected the expression of PAG1 in normal and tumor tissues. The PAG1 overexpressed OSCC cell lines were constructed by lentivirus transfection. Cell Counting Kit-8 assay (CCK-8), clone formation and flow cytometry evaluated the impact of PAG1 on the proliferation and apoptosis of OSCC cells. RNA sequencing (RNA-seq) detected the changes in intracellular genes, and transmission electron microscope (TEM) was used to compare the number of autophagosomes in OSCC cells between Negative and PAG1 group. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blot were used to determine the expression of signaling pathway-related mRNA and proteins respectively. RESULTS: In contrast to the normal tissues, PAG1 expression was significantly downregulated in tumor tissues. Treatment with lentivirus transfection, the expression of PAG1 in the OSCC cell lines was increase. Notably, transfected with PAG1-overexpressing lentivirus cells inhibited the proliferation of OSCC cells and promoted OSCC cells apoptosis. RNA-seq revealed that PAG1 mainly modulated the mitophagy and autophagy pathway, and many autophagosomes were observed in the PAG1 group using TEM. Mechanistically, we found that PAG1 upregulated the expression of autophagy related factors through inhibiting PI3K/Akt/mTOR signal pathway activation. CONCLUSION: Overexpression of PAG1 inhibited OSCC progression by activating autophagy, its mechanism might be related to inhibition of PI3K/Akt/mTOR signal pathway phosphorylation.

Learning With Nested Scene Modeling and Cooperative Architecture Search for Low-Light Vision.

Images captured from low-light scenes often suffer from severe degradations, including low visibility, color casts, intensive noises, etc. These factors not only degrade image qualities, but also affect the performance of downstream Low-Light Vision (LLV) applications. A variety of deep networks have been proposed to enhance the visual quality of low-light images. However, they mostly rely on significant architecture engineering and often suffer from the high computational burden. More importantly, it still lacks an efficient paradigm to uniformly handle various tasks in the LLV scenarios. To partially address the above issues, we establish Retinex-inspired Unrolling with Architecture Search (RUAS), a general learning framework, that can address low-light enhancement task, and has the flexibility to handle other challenging downstream vision tasks. Specifically, we first establish a nested optimization formulation, together with an unrolling strategy, to explore underlying principles of a series of LLV tasks. Furthermore, we design a differentiable strategy to cooperatively search specific scene and task architectures for RUAS. Last but not least, we demonstrate how to apply RUAS for both low- and high-level LLV applications (e.g., enhancement, detection and segmentation). Extensive experiments verify the flexibility, effectiveness, and efficiency of RUAS.

Deep learning identifies robust gender differences in functional brain organization and their dissociable links to clinical symptoms in autism.

BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous disorder that affects nearly 1 in 189 females and 1 in 42 males. However, the neurobiological basis of gender differences in ASD is poorly understood, as most studies have neglected females and used methods ill-suited to capture such differences. AIMS: To identify robust functional brain organisation markers that distinguish between females and males with ASD and predict symptom severity. METHOD: We leveraged multiple neuroimaging cohorts (ASD n = 773) and developed a novel spatiotemporal deep neural network (stDNN), which uses spatiotemporal convolution on functional magnetic resonance imaging data to distinguish between groups. RESULTS: stDNN achieved consistently high classification accuracy in distinguishing between females and males with ASD. Notably, stDNN trained to distinguish between females and males with ASD could not distinguish between neurotypical females and males, suggesting that there are gender differences in the functional brain organisation in ASD that differ from normative gender differences. Brain features associated with motor, language and visuospatial attentional systems reliably distinguished between females and males with ASD. Crucially, these results were observed in a large multisite cohort and replicated in a fully independent cohort. Furthermore, brain features associated with the motor network's primary motor cortex node predicted the severity of restricted/repetitive behaviours in females but not in males with ASD. CONCLUSIONS: Our replicable findings reveal that the brains of females and males with ASD are functionally organised differently, contributing to their clinical symptoms in distinct ways. They inform the development of gender-specific diagnoses and treatment strategies for ASD, and ultimately advance precision psychiatry.

Stability criteria on delay-dependent robust stability for uncertain neutral stochastic nonlinear systems with time-delay.

This work mainly studies the robust stability analysis and design of a controller for uncertain neutral stochastic nonlinear systems with time-delay. Using a modified Lyapunov-Krasovskii functional and the free-weighting matrices technique, we establish some new delay-dependent criteria in terms of linear matrix inequality (LMI). The innovative point of this work is that we generalize the robust stability analysis of nonlinear stochastic time-delay systems to the uncertain neutral stochastic systems. Due to the added derivative term of time-delay, the proposed scheme can be applied more widely. Finally, numerical examples are provided to validate the derived results.

Drosophila sbo regulates lifespan through its function in the synthesis of coenzyme Q in vivo.

CoQ is an essential electron carrier in the mitochondrial respiratory chain of both eukaryotes and prokaryotes. It consists of a benzoquinone head group and a hydrophobic polyisoprenoid tail. The genes (COQ1-9) involved in CoQ biosynthesis have been characterized in yeast. In this study, we generated and molecularly characterized a mutant allele of a novel Drosophila gene, sbo, which encodes a protein that is predicted to catalyze the prenylation of p-hydroxybenzoate with the isoprenoid chain during the process of CoQ synthesis. Expression of sbo in yeast rescues the lethality of ∆COQ2 mutant cells, indicating that sbo is a functional homolog of COQ2. HPLC results show that the levels of CoQ(9) and CoQ(10) were significantly reduced in sbo heterozygous adult flies. Furthermore, the mean lifespans of males and females heterozygous for sbo are extended by 12.5% and 30.8%, respectively. Homozygous sbo animals exhibit reduced activities of the insulin/insulin-like growth factor signaling (IIS) pathway. Taken together, we conclude that sbo is an essential gene for Drosophila development, mutation of which leads to an extension of lifespan most likely by altering endogenous CoQ biosynthesis.