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Cancer-associated fibroblasts (CAFs) are an essential component in the tumor microenvironment and have been reported to contribute to tumor progression through many mechanisms; however, the detailed mechanism underlying the immune-suppression effect of CAFs is not clearly defined. In this study, human breast cancer-derived CAFs were cultured, and CAF-derived exosomes in a culture medium were isolated. Using a miRNA profiles assay, we identify a significantly higher level of microRNA-92 isolated in CAFs exosomes. After treatment by CAF-derived exosomes, breast cancer cells express higher programmed cell death receptor ligand 1 (PD-L1), accompanied with increased miR-92 expression. Increased PD-L1 expression, which was induced by CAF-derived exosomes, significantly promotes apoptosis and impaired proliferation of T cells. The underlying mechanism of this effect was studied, proliferation and migration of breast cancer cells were increased after the transfection of miR-92, LATS2 was recognized as a target gene of miR-92, and further confirmed by a luciferase assay. Immunoprecipitation showed that LATS2 can interact with YAP1, chromatin immunoprecipitation confirmed that after nuclear translocation YAP1 could bind to the enhancer region of PD-L1 to promotes transcription activity. Furthermore, the animal study confirmed that CAFs significantly promoted tumor progression and impaired the function of tumor-infiltrated immune cells . Our data revealed a novel mechanism that can induce immune suppression in the tumor microenvironment.

Human papillomavirus (HPV) is the most prevalent sexually transmitted infection. Copper is essential for immune function, but its association with HPV infection remains unclear. This study aims to investigate the relationship between dietary copper intake and HPV infection. This cross-sectional study analyzed 8,071 participants from the National Health and Nutrition Examination Survey (2003-2016). Copper intake was assessed using two 24-hour recalls, and HPV status was confirmed by DNA testing. Weighted multivariable logistic regression and restricted cubic splines (RCS) were used. After adjusting for multiple confounders, dietary copper intake was significantly inversely associated with vaginal HPV infection (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.67-0.92). Compared with women in the lowest quartile of dietary copper intake, those in the highest quartile had a lower adjusted OR for vaginal HPV infection (OR, 0.60; 95% CI, 0.48-0.73). RCS analysis revealed an L-shaped association with a threshold at 1.2 mg/day of copper intake. Subgroup analyses showed that marital status moderated the association between copper intake and HPV infection (P for interaction < 0.001), with significance in those married or living with a partner but not in those living alone. An L-shaped association was observed between copper intake and HPV infection, suggesting that maintaining an optimal level of copper intake may be associated with reduced risk of HPV infection and related diseases.

The dorsal striatum has emerged as a key region in sensory-guided, reward-driven decision making. A posterior sub-region of the dorsal striatum, the auditory striatum, receives convergent projections from both auditory thalamus and auditory cortex. How these pathways contribute to auditory striatal activity and function remains largely unknown. Here we show that chemogenetic inhibition of the projections from either the medial geniculate body (MGB) or primary auditory cortex (ACx) to auditory striatum in mice impairs performance in an auditory frequency discrimination task. While recording striatal sound responses, we find that transiently silencing the MGB projection reduced sound responses across a wide-range of frequencies in striatal medium spiny neurons. In contrast, transiently silencing the primary ACx projection diminish sound responses preferentially at the best frequencies in striatal medium spiny neurons. Together, our findings reveal that the MGB projection mainly functions as a gain controller, whereas the primary ACx projection provides tuning information for striatal sound representations. The precise role of auditory cortical and thalamic projections in the representation of sound in the auditory striatum is not known. Here, the authors show that silencing thalamic inputs lowers the gain of sound-evoked responses while cortical inputs only affect the best frequency responses of striatal neurons.

Epigenetic mechanisms such as DNA methylation have the potential to affect organism acclimatization and adaptation to environmental changes by influencing their phenotypic plasticity; however, little is known about the role of methylation in the adaptive phenotypic divergence of marine invertebrates. Therefore, in this study, a typical intertidal species, the Pacific oyster (Crassostrea gigas), was selected to investigate the epigenetic mechanism of phenotypic plasticity in marine invertebrates. Intertidal and subtidal oysters subjected to one-generation common garden experiments and exhibited phenotypic divergence were used. The methylation landscape of both groups of oysters was investigated under temperate and high temperature. The two tidal oysters exhibited divergent methylation patterns, regardless of the temperature, which was mainly original environment-induced. Intertidal samples exhibited significant hypomethylation and more plasticity of methylation in response to heat shock, while subtidal samples showed hypermethylation and less plasticity. Combined with RNA-seq data, a positive relationship between methylation and expression in gene bodies was detected on a genome-wide scale. In addition, approximately 11% and 7% of differentially expressed genes showed significant methylation variation under high temperatures in intertidal and subtidal samples, respectively. Genes related to apoptosis and organism development may be regulated by methylation in response to high temperature in intertidal oysters, whereas oxidation-reduction and ion homeostasis-related genes were involved in subtidal oysters. The results also suggest that DNA methylation mediates phenotypic divergence in oysters adapting to different environments. This study provides new insight into the epigenetic mechanisms underlying phenotypic plasticity in adaptation to rapid climate change in marine organisms.

Microglia are important for brain homeostasis and immunity, but their role in regulating vigilance remains unclear. We employed genetic, physiological, and metabolomic methods to examine microglial involvement in the regulation of wakefulness and sleep. Microglial depletion decreased stable nighttime wakefulness in mice by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Metabolomic analysis revealed that the sleep-wake behavior closely correlated with diurnal variation of the brain ceramide, which disappeared in microglia-depleted mice. Ceramide preferentially influenced microglia in the thalamic reticular nucleus (TRN), and local depletion of TRN microglia produced similar impaired wakefulness. Chemogenetic manipulations of anterior TRN neurons showed that they regulated transitions between wakefulness and NREM sleep. Their firing capacity was suppressed by both microglial depletion and added ceramide. In microglia-depleted mice, activating anterior TRN neurons or inhibiting ceramide production both restored stable wakefulness. These findings demonstrate that microglia can modulate stable wakefulness through anterior TRN neurons via ceramide signaling. Here, the authors show that microglia depletion results in unstable wakefulness and altered levels of ceramide, influencing microglia in the mouse thalamic reticular nucleus (TRN). Stable wakefulness can be restored by activation of the TRN or inhibition of ceramide production in the mouse brain.

Background Revealing the mechanical role of long non-coding RNAs (lncRNAs) in tumorigenesis can contribute to novel therapeutic target for cancers. The regulatory role of linc01134 in hepatocellular carcinoma (HCC) has not been studied yet. Materials and methods qRT-PCR and western blot were conducted to measure relevant RNA and protein expressions. CCK-8, colony formation, EdU, flow cytometry, wound-healing, transwell assays and xenograft experiments were performed to determine the role of linc01134 in HCC. ChIP and luciferase reporter assays were performed to analyze the effects of Yin Yang-1 (YY1) on linc01134 transcription activity. Relevant mechanical experiments were performed to verify interaction between relative genes. Results YY1 enhanced linc01134 transcription by interacting with linc01134 promoter. Knockdown of linc01134 inhibited proliferation, migration and epithelial-mesenchymal transition (EMT), yet promoting apoptosis in HCC cells. Mechanically, linc01134 acted as miR-324-5p sponge and interacted with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to increase the stability of YY1 mRNA expression. Up-regulated YY1 continuously stimulated linc01134 expression by enhancing linc01134 promoter activity, forming a positive feedback loop. Conclusion Linc01134/miR-324-5p/IGF2BP1/YY1 feedback loop mediates HCC progression, which possibly provide prognosis and treatment target of HCC.

Background Biological aging, defined as the biological age (BA) or phenotypic age (PA) exceeding the chronological age (CA), is a key indicator of premature aging. Obesity accelerates aging; however, the effect of Body Roundness Index (BRI), an indicator of abdominal obesity, combined with sex or Ascorbic acid (Asc), on biological aging remains unclear. This study examined the association between BRI and biological aging, its interaction with sex and Asc intake, and its mediating mechanisms. Methods Data from the 1999–2018 U.S. National Health and Nutrition Examination Survey (NHANES) formed the basis of this study. Biological aging is characterized by BA or PA surpassing CA. Association between the BRI and biological aging was evaluated using multivariable-adjusted weighted regression. To assess for nonlinearity, restricted cubic splines were utilized, while interactions were investigated through both additive and multiplicative analyses. The bootstrap method was used to examine the potential mediating effects of biomarkers of metabolic dysfunction, oxidative stress, and protective pathways. Results The final analysis included 14,337 U.S. adults (mean age 47.5 years; 50.27% women). A total of 49.32% of the participants showed signs of biological aging, with BRI being positively associated with biological aging in a nonlinear manner, including a threshold effect. The increase in the risk per BRI unit was more significant in women, and high doses of Asc reduced the risk of biological aging associated with increased BRI. Mediation analysis indicated that the association between BRI and accelerated aging was partly mediated by metabolic dysfunction (mediated by the triglyceride-glucose index [18.73%] and by triglycerides [9.21%], oxidative stress mediated by uric acid [17.92%] and by white blood cell count [5.80%], and depletion of protective factors mediated by vitamin D [− 3.85%] and by high-density lipoprotein [− 4.24%]). A sensitivity analysis confirmed the reliability of the findings. Conclusions A higher BRI showed a nonlinear positive association with accelerated biological aging, a relationship that appears to be modified by female sex and Asc intake. Clinical approaches targeting metabolic dysfunction, oxidative stress, and antioxidant and vasoprotective reserves may help combat obesity-related aging. BRI thresholds enable early identification of individuals at high risk for personalized interventions. Graphical abstract

Because of the limited treatment strategy of gliomas, the key of diagnosis and treatment is finding new molecular biomarkers. Here, we explored the potential of β2-microglobulin (B2M) to serve as a hopeful candidate for immunotherapy or diagnostic biomarker in gliomas. The genomic profiles, clinical characteristics, and immune signatures were analyzed based on TCGA and CGGA databases. We carried out the whole statistical analyses using R project. High B2M expression correlated with worse prognosis. Somatic mutations of gliomas with high B2M expression are associated with PTEN deletion and EGFR amplification. Isocitrate dehydrogenase (IDH) mutations accounted for 82% in gliomas with low B2M expression. In addition, B2M positively correlated with ESTIMATE scores, interacted with infiltrating immune and stromal cell types. B2M also suppressed anti-tumor immunity through immune related processes. Meanwhile, B2M was associated with immune checkpoint molecules and inflammatory activities. Finally, functional annotation of the identified B2M related genes verified that B2M was a potential candidate for immunotherapy. We confirmed that B2M played a critical role in tumor progression, patient prognosis and immunotherapy of gliomas.

l -Lactate is increasingly appreciated as a key metabolite and signaling molecule in mammals. However, investigations of the inter- and intra-cellular dynamics of l -lactate are currently hampered by the limited selection and performance of l -lactate-specific genetically encoded biosensors. Here we now report a spectrally and functionally orthogonal pair of high-performance genetically encoded biosensors: a green fluorescent extracellular l -lactate biosensor, designated eLACCO2.1, and a red fluorescent intracellular l -lactate biosensor, designated R-iLACCO1. eLACCO2.1 exhibits excellent membrane localization and robust fluorescence response. To the best of our knowledge, R-iLACCO1 and its affinity variants exhibit larger fluorescence responses than any previously reported intracellular l -lactate biosensor. We demonstrate spectrally and spatially multiplexed imaging of l -lactate dynamics by coexpression of eLACCO2.1 and R-iLACCO1 in cultured cells, and in vivo imaging of extracellular and intracellular l -lactate dynamics in mice. l -Lactate is increasingly recognized as a key metabolite and signalling molecule in mammals, but the methods to investigate it in vivo have been limited. Here, authors report a pair of improved biosensors—one green and one red—for visualizing l -lactate both inside and outside of cells.

This study describes the role of circ_0008039 in breast cancer. We found that high expression of circ_0008039 was significantly associated with lymph node metastasis and tumor stage of breast cancer patients, and circ_0008039 knockdown could inhibit breast cancer cell proliferation, invasion, and glucose metabolism by upregulating miR‐140‐3p and downregulating SKA2. Circular RNAs (circRNAs) have been shown to modulate gene expression and participate in the development of multiple malignancies. The purpose of this study was to investigate the role of circ_0008039 in breast cancer (BC). The expression of circ_0008039, miR‐140‐3p, and spindle and kinetochore‐associated protein 2 (SKA2) was detected by qRT‐PCR. Cell viability, colony formation, migration, and invasion were evaluated using methylthiazolyldiphenyl‐tetrazolium bromide (MTT) assay, colony formation assay, and transwell assay, respectively. Glucose consumption and lactate production were measured using commercial kits. Protein levels of hexokinase II (HK2) and SKA2 were determined by western blot. The interaction between miR‐140‐3p and circ_0008039 or SKA2 was verified by dual‐luciferase reporter assay. Finally, a mouse xenograft model was established to investigate the roles of circ_0008039 in BC in vivo. We found that circ_0008039 and SKA2 were upregulated in BC tissues and cells, while miR‐140‐3p was downregulated. Knockdown of circ_0008039 suppressed BC cell proliferation, migration, invasion, and glycolysis. Moreover, miR‐140‐3p could bind to circ_0008039 and its inhibition reversed the inhibitory effect of circ_0008039 interference on proliferation, migration, invasion, and glycolysis in BC cells. SKA2 was verified as a direct target of miR‐140‐3p and its overexpression partially inhibited the suppressive effect of miR‐140‐3p restoration in BC cells. Additionally, circ_0008039 positively regulated SKA2 expression by sponging miR‐140‐3p. Consistently, silencing circ_0008039 restrained tumor growth via increasing miR‐140‐3p and decreasing SKA2. In conclusion, circ_0008039 downregulation suppressed BC cell proliferation, migration, invasion, and glycolysis partially through regulating the miR‐140‐3p/SKA2 axis, providing an important theoretical basis for treatment of BC.