The role of the gut microbiome in enhancing the efficacy of anticancer treatments like chemotherapy and radiotherapy is well acknowledged. However, there is limited empirical evidence on its predictive capabilities for neoadjuvant immunochemotherapy (NICT) responses in esophageal squamous cell carcinoma (ESCC). Our study fills this gap by comprehensively analyzing the gut microbiome’s influence on NICT outcomes. We analyzed 16S rRNA gene sequences from 136 fecal samples from 68 ESCC patients before and after NICT, along with 19 samples from healthy controls. After NICT, marked microbiome composition changes were noted, including a decrease in ESCC-associated pathogens and an increase in beneficial microbes such as Limosilactobacillus, Lacticaseibacillus, and Staphylococcus. Baseline microbiota profiles effectively differentiated responders from nonresponders, with responders showing higher levels of short-chain fatty acid (SCFA)-producing bacteria such as Faecalibacterium, Eubacterium_eligens_group, Anaerostipes, and Odoribacter, and nonresponders showing increases in Veillonella, Campylobacter, Atopobium, and Trichococcus. We then divided our patient cohort into training and test sets at a 4:1 ratio and utilized the XGBoost-RFE algorithm to identify 7 key microbial biomarkers—Faecalibacterium, Subdoligranulum, Veillonella, Hungatella, Odoribacter, Butyricicoccus, and HT002. A predictive model was developed using LightGBM, which achieved an area under the receiver operating characteristic curve (AUC) of 86.8% [95% confidence interval (CI), 73.8% to 99.4%] in the training set, 76.8% (95% CI, 41.2% to 99.7%) in the validation set, and 76.5% (95% CI, 50.4% to 100%) in the testing set. Our findings underscore the gut microbiome as a novel source of biomarkers for predicting NICT responses in ESCC, highlighting its potential to enhance personalized treatment strategies and advance the integration of microbiome profiling into clinical practice for modulating cancer treatment responses.

Cisplatin is widely used to treat osteosarcoma, but recurrent cases often develop resistance, allowing the disease to progress and complicating clinical management. This study aimed to elucidate the immune microenvironment of osteosarcoma, providing insights into the mechanisms of recurrence and identifying potential therapeutic strategies. By analyzing multiple single-cell and bulk RNA-sequencing datasets, we discovered that the SUMOylation-related gene ZNF451 promotes osteosarcoma recurrence and alters its immune microenvironment. ZNF451 was found to importantly enhance the growth, migration, and invasion of resistant cells while also reducing their sensitivity to cisplatin and lowering their apoptosis rate. Moreover, our data indicated that ZNF451 plays a crucial role in bone resorption and epithelial–mesenchymal transition. ZNF451 also regulates CD8⁺ T cell function, leading to their exhaustion and transition to the CD8T.EXH state. Additionally, β-cryptoxanthin has been identified as a potential therapeutic agent that inhibits osteosarcoma progression by targeting ZNF451. In summary, these findings highlight the critical role of ZNF451 in promoting osteosarcoma progression and underscore its potential as a therapeutic target and biomarker for osteosarcoma.

Achieving rubber-like stretchability in cellulose ionogels presents a substantial challenge due to the intrinsically extended chain configuration of cellulose. Inspired by the molecular configuration of natural rubber, we address this challenge by using cyanoethyl as a substitute for 1.5 hydroxyl on the D-glucose unit of cellulose. This strategy innovatively triggers the transformation of cellulose molecules into a coiled chain configuration, facilitating the creation of an ultra-stretchable ionogel free from any petrochemical polymers. The resultant ionogel demonstrates mechanical ductility comparable to that of a rubber band, achieving an elongation strain of nearly 1,000% while maintaining a tensile strength of up to 1.8 MPa and exhibiting a biomodulus akin to that of human skin, recorded at 63 kPa. Additionally, this stretchable ionogel presents skin-like self-healing behavior, favorable biocompatibility, and noteworthy thermoelectric properties, highlighted by a Seebeck coefficient of approximately 68 mV K⁻¹. This study delineates a feasible molecular approach for developing stretchable ionogels from biomass resources, potentially revolutionizing self-powered stretchable electronics for integration with human tissues and skin.

Tree shrews (TSs) possess a highly developed visual system. Here, we establish an age-related single-cell RNA sequencing atlas of retina cells from 15 TSs, covering 6 major retina cell classes and 3 glial cell types. An age effect is observed on the cell subset composition and gene expression pattern. We then verify the cell subtypes and identify specific markers in the TS retina including CA10 for bipolar cells, MEGF11 for H1 horizontal cells, and SLIT2, RUNX1, FOXP2, and SPP1 for retinal ganglion cell subpopulations. The cross-species analysis elucidates the cell type-specific transcriptional programs, different cell compositions, and cell communications. The comparisons also reveal that TS cones and subclasses of bipolar and amacrine cells exhibit the closest relationship with humans and macaques. Our results suggests that TS could be used as a better disease model to understand age-dependent cellular and genetic mechanisms of the retina, particularly for the retinal diseases associated with cones.

Postpartum depression (PPD) represents a important emotional disorder emerging after childbirth, characterized by its complex etiology and challenging management. Despite extensive preclinical and clinical investigations underscoring the role of estrogen fluctuations and estrogen receptor genes in PPD, the precise mechanisms underpinning this condition have remained elusive. In our present study, animal behavioral studies have elucidated a tight link between the aberrant expression of ESR2, miR-10a-5p, and BDNF in the prefrontal cortex of mice exhibiting postpartum depressive-like behavior, shedding light on the potential molecular pathways involved. Integrating bioinformatics, in vivo, and cell transfection methodologies has unraveled the intricate molecular interplay between ESR2, miR-10a-5p, and BDNF. We identified ESR2 as a negative transcription factor that down-regulates miR-10a transcription, while miR-10a-5p serves as a negative regulator that suppresses BDNF expression. This molecular triad contributes to the pathogenesis of PPD by affecting synaptic plasticity, as evidenced by alterations in synapse-related proteins (e.g., SYP, SYN, and PSD95) and glutamate receptor expression. Additionally, primary neuron culture studies have confirmed the critical roles of ESR2 and miR-10a-5p in maintaining neuronal growth and morphology. Therapeutic interventions, including stereotactic and intranasal administration of antagomir or BDNF, have demonstrated significant potential in treating PPD, highlighting the therapeutic implications of targeting the negative transcriptional and regulatory interactions between ESR2, miR-10a-5p, and BDNF. Our findings endorse the hypothesis that estrogen fluctuations and estrogen receptor gene activity are pivotal stressors and risk factors for PPD, affecting central nervous system functionality and precipitating depressive behaviors postpartum.

Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent malignant tumor of the urinary system. While tyrosine kinase inhibitors (TKIs) are currently the first-line treatments for advanced/metastatic ccRCC, patients often develop resistance after TKI therapy. Lipid metabolic reprogramming, a hallmark of tumor progression, contributes to acquired drug resistance in various malignant tumors. Mitophagy, a process that maintains mitochondrial homeostasis, aids tumor cells in adapting to microenvironmental changes and consequently developing drug resistance. Solute carrier family 27 member 3 (SLC27A3), highly expressed in lipid-rich tumors like ccRCC, has been associated with poor prognosis. However, the impact of SLC27A3 and the transcription factor complex containing STAT2 on lipid metabolic reprogramming, mitophagy in ccRCC, and their role in TKI resistance remain unexplored. Methods: 786-O to pazopanib resistance was induced by gradient increase of concentration, and the genes related to lipid metabolism were screened by RNA sequencing. Bioinformatics was used to analyze the differential expression of SLC27A3 and its effect on patient prognosis, and to predict the activated pathway in pazopanib-resistant cells. Lipid droplets (LDs) were detected by Red Oil O and BODIPY probe. Micro-targeted lipidomic of acyl-coenzyme A (CoA) and lipid metabolomics were performed to screen potential metabolites of SLC27A3. The differential expression of SLC27A3 was detected in clinical samples. The differential expression of SLC27A3 and its effect on drug resistance of ccRCC tumor were detected in vitro and in vivo. Mitophagy was detected by electron microscopy, Mtphagy probe, and Western blot. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were detected by JC-1 and DCF probes. The binding site of the transcription factor complex to the SLC27A3 promoter was detected by dual-luciferase reporter gene assay. Results: SLC27A3, highly expressed in lipid-rich tumors such as ccRCC and glioblastoma, predicts poor prognosis. SLC27A3 expression level also increased in pazopanib-resistant 786-O cells (786-O-PR) with more LD accumulation compared to parental cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis from RNA sequencing showed that PINK1/Parkin-mediated mitophagy pathway was enriched in 786-O-PR. Knockdown of SLC27A3 markedly suppressed LD accumulation and mitophagy, and overcame pazopanib resistance in vitro and in vivo. Moreover, SLC27A3 functions as an acyl-CoA ligase catalyzing the formation of acyl-CoA, which refers to fatty acid oxidation accompanied by ROS production and synthesis of lipid. Overproduced acyl-CoA oxidation in mitochondria resulted in MMP decrease and amounts of ROS production, subsequently triggering PINK1/Parkin-mediated mitophagy. Moreover, mitophagy inhibition led to more ROS accumulation and cell death, indicating that mitophagy can keep ROS at an appropriate level by negative feedback. Mitophagy, simultaneously, prevented fatty acid oxidation in mitochondria by consuming CPT1A, forcing synthesis of triglycerides and cholesterol esters stored in LDs by transforming acyl-CoA, to support ccRCC progression. Besides, we found that STAT2 expression was positively correlated to SLC27A3. Transcriptional factor complex containing STAT2 could bind to the promoter of SLC27A3 mRNA to promote SLC27A3 transcription proved by dual-luciferase reporter assay, which also regulated LD metabolism and activated mitophagy during pazopanib resistance. Conclusion: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for β-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid β-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. Furthermore, STAT2 was identified as a core component of a potential upstream transcriptional factor complex for SLC27A3. Our findings shed new light on the underlying mechanism of SLC27A3 in ccRCC TKI resistance, which may provide a novel therapeutic target for the management of ccRCC.

The sensorimotor cortex participates in diverse functions with different reciprocally connected subregions and projection-defined pyramidal neuron types therein, while the fundamental organizational logic of its circuit elements at the single-cell level is still largely unclear. Here, using mouse Cre driver lines and high-resolution whole-brain imaging to selectively trace the axons and dendrites of cortical pyramidal tract (PT) and intratelencephalic (IT) neurons, we reconstructed the complete morphology of 1,023 pyramidal neurons and generated a projectome of 6 subregions within the sensorimotor cortex. Our morphological data revealed substantial hierarchical and layer differences in the axonal innervation patterns of pyramidal neurons. We found that neurons located in the medial motor cortex had more diverse projection patterns than those in the lateral motor and sensory cortices. The morphological characteristics of IT neurons in layer 5 were more complex than those in layer 2/3. Furthermore, the soma location and morphological characteristics of individual neurons exhibited topographic correspondence. Different subregions and layers were composed of different proportions of projection subtypes that innervate downstream areas differentially. While the axonal terminals of PT neuronal population in each cortical subregion were distributed in specific subdomains of the superior colliculus (SC) and zona incerta (ZI), single neurons selectively innervated a combination of these projection targets. Overall, our data provide a comprehensive list of projection types of pyramidal neurons in the sensorimotor cortex and begin to unveil the organizational principle of these projection types in different subregions and layers.

Given the high malignancy of liver cancer and the liver’s unique role in immune and metabolic regulation, current treatments have limited efficacy, resulting in a poor prognosis. Hydrogels, soft 3-dimensional network materials comprising numerous hydrophilic monomers, have considerable potential as intelligent drug delivery systems for liver cancer treatment. The advantages of hydrogels include their versatile delivery modalities, precision targeting, intelligent stimulus response, controlled drug release, high drug loading capacity, excellent slow-release capabilities, and substantial potential as carriers of bioactive molecules. This review presents an in-depth examination of hydrogel-assisted advanced therapies for hepatocellular carcinoma, encompassing small-molecule drug therapy, immunotherapy, gene therapy, and the utilization of other biologics. Furthermore, it examines the integration of hydrogels with conventional liver cancer therapies, including radiation, interventional therapy, and ultrasound. This review provides a comprehensive overview of the numerous advantages of hydrogels and their potential to enhance therapeutic efficacy, targeting, and drug delivery safety. In conclusion, this review addresses the clinical implementation of hydrogels in liver cancer therapy and future challenges and design principles for hydrogel-based systems, and proposes novel research directions and strategies.

Cognitive dysfunction stands as a prevalent and consequential non-motor manifestation in Parkinson’s disease (PD). Although dysfunction of the olfactory system has been recognized as an important predictor of cognitive decline, the exact mechanism by which aberrant olfactory circuits contribute to cognitive dysfunction in PD is unclear. Here, we provide the first evidence for abnormal functional connectivity across olfactory bulb (OB) and piriform cortex (PC) or entorhinal cortex (EC) by clinical fMRI, and dysfunction of neural coherence in the olfactory system in PD mice. Moreover, we discovered that 2 subpopulations of mitral/tufted (M/T) cells in OB projecting to anterior PC (aPC) and EC precisely mediated the process of cognitive memory respectively by neural coherence at specific frequencies in mice. In addition, the transcriptomic profiling analysis and functional genetic regulation analysis further revealed that biorientation defective 1 (Bod1) may play a pivotal role in encoding OB^M/T-mediated cognitive function. We also verified that a new deep brain stimulation protocol in OB ameliorated the cognitive function of Bod1-deficient mice and PD mice. Together, aberrant coherent activity in the olfactory system can serve as a biomarker for assessing cognitive function and provide a candidate therapeutic target for the treatment of PD.