Smooth-Muscle-Cell-Specific Deletion of CD38 Protects Mice from AngII-Induced Abdominal Aortic Aneurysm through Inhibiting Vascular Remodeling.

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.

A lactate metabolism-related signature predicting patient prognosis and immune microenvironment in ovarian cancer.

Introduction: Ovarian cancer (OV) is a highly lethal gynecological malignancy with a poor prognosis. Lactate metabolism is crucial for tumor cell survival, proliferation, and immune evasion. Our study aims to investigate the role of lactate metabolism-related genes (LMRGs) in OV and their potential as biomarkers for prognosis, immune microenvironment, and immunotherapy response. Methods: Ovarian samples were collected from the TCGA cohort. And 12 lactate-related pathways were identified from the MsigDB database. Differentially expressed genes within these pathways were designated as LMRGs, which undergo unsupervised clustering to identify distinct clusters based on LMRGs. Subsequently, we assessed survival outcomes, immune cell infiltration levels, Hallmaker pathway activation patterns, and chemotaxis among different subtypes. After conducting additional unsupervised clustering based on differentially expressed genes (DEGs), significant differences in the expression of LMRGs between the two clusters were observed. The differentially expressed genes were subjected to subsequent functional enrichment analysis. Furthermore, we construct a model incorporating LMRGs. Subsequently, the lactate score for each tumor sample was calculated based on this model, facilitating the classification of samples into high and low groups according to their respective lactate scores. Distinct groups examined disparities in survival prognosis, copy number variation (CNV), single nucleotide variation (SNV), and immune infiltration. The lactate score served as a quantitative measure of OV's lactate metabolism pattern and an independent prognostic factor. Results: This study investigated the potential role of LMRGs in tumor microenvironment diversity and prognosis in OV, suggesting that LMRGs play a crucial role in OV progression and the tumor microenvironment, thus serving as novel indicators for prognosis, immune microenvironment status, and response to immunotherapy.

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease.

The development of nonalcoholic fatty liver disease (NAFLD) has been reported to be caused by sphingolipid family inducing insulin resistance, mitochondrial dysfunction, and inflammation, which can be regulated by multiple sphingolipid metabolic pathways. This study aimed to explore the molecular mechanism of crucial sphingolipid metabolism related genes (SMRGs) in NAFLD. Firstly, the datasets (GSE48452, GSE126848, and GSE63067) from the Gene Expression Omnibus database and sphingolipid metabolism genes (SMGs) from previous research were collected for this study. The differentially expressed genes (DEGs) between different NAFLD and controls were acquired through "limma," and the SMRGs were authenticated via weighted gene co-expression network analysis (WGCNA). After overlapping the DEGs and SMRGs, the causality between the intersection genes (DE-SMRGs) and NAFLD was explored to sort out the candidate biomarkers by Mendelian randomization (MR) study. The receiver operating characteristic (ROC) curves of candidate biomarkers in GSE48452 and GSE126848 were yielded to determine the biomarkers, followed by the nomogram construction and enrichment analysis. Finally, the immune infiltration analysis, the prediction of transcription factors (TFs) and drugs targeting biomarkers were put into effect. A total of 23 DE-SMRGs were acquired based on the differential analysis and weighted gene co-expression network analysis (WGCNA), of which 3 DE-SMRGs (CD37, CXCL9 and IL7R) were picked out for follow-up analysis through univariate and multivariate MR analysis. The values of area under ROC curve of CD37 and CXCL9 were >0.7 in GSE48452 and GSE126848, thereby being regarded as biomarkers, which were mainly enriched in amino acid metabolism. With respect to the Spearman analysis between immune cells and biomarkers, CD37 and CXCL9 were significantly positively associated with M1 macrophages (P < .001), whose proportion was observably higher in NAFLD patients compared with controls. At last, TFs (ZNF460 and ZNF384) of CD37 and CXCL9 and a total of 79 chemical drugs targeting CD37 and CXCL9 were predicted. This study mined the pivotal SMRGs, CD37 and CXCL9, and systematically explored the mechanism of action of both biomarkers based on the public databases, which could tender a fresh reference for the clinical diagnosis and therapy of NAFLD.

Immune landscape and heterogeneity of cervical squamous cell carcinoma and adenocarcinoma.

Despite the differences in disease outcomes and pathological features between cervical squamous cell carcinoma (CSCC) and adenocarcinoma (ADC), the molecular characteristics in immune heterogeneity of the tumor microenvironment remain unclear. Here, we explored the immune landscape and heterogeneity between CSCC and ADC. Gene expression and clinical characteristics of cervical carcinoma from The Cancer Genome Atlas (TCGA) were downloaded. Differentially expressed genes (DEGs), immune cell infiltration, and pathway enrichment analyses were used to explore the immune landscape and heterogeneity between CSCC and ADC. Furthermore, distinct immune signatures between CSCC and ADC were validated based on clinical samples. In total, 4,132 upregulated DEGs and 2,307 down-regulated DEGs were identified between CSCC and ADC, with enrichments in immune related-pathways in CSCC. In addition, 54 hub DEGs correlated with patients' prognosis and immunocytes infiltration were identified. The CSCC patients had a higher ImmuneScore and more abundant immunocytes infiltration compared to ADC patients, as validated by immunohistochemistry (IHC) and multicolor immunofluorescence (mIF) analyses of collected samples. Furthermore, CSCC displayed higher inhibitory immune checkpoints expression, tumor mutation burden (TMB), and microsatellite instability (MSI) compared to ADC, which indicated CSCC patients were more likely to benefit from immunotherapy. In summary, our results revealed the huge immune heterogeneity between CSCC and ADC, and provided guidance for immunotherapy selection for different pathological types of cervical cancer.

YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths.

N6-methyladenosine (m6A) is a critical regulator in the fate of RNA, but whether and how m6A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m6A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.

CD38 Deficiency Alleviates Diabetic Cardiomyopathy by Coordinately Inhibiting Pyroptosis and Apoptosis.

Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by cardiomyocyte apoptosis, local inflammation, oxidative stress, and myocardial fibrosis. CD38, a main hydrolase of NAD+ in mammals, plays an important role in various cardiovascular diseases, according to our previous studies. However, the role of CD38 in diabetes-induced cardiomyopathy is still unknown. Here, we report that global deletion of the CD38 gene significantly prevented diabetic cardiomyopathy induced by high-fat diet plus streptozotocin (STZ) injection in CD38 knockout (CD38-KO) mice. We observed that CD38 expression was up-regulated, whereas the expression of Sirt3 was down-regulated in the hearts of diabetic mice. CD38 deficiency significantly promoted glucose metabolism and improved cardiac functions, exemplified by increased left ventricular ejection fraction and fractional shortening. In addition, we observed that CD38 deficiency markedly decreased diabetes or high glucose and palmitic acid (HG + PA)-induced pyroptosis and apoptosis in CD38 knockout hearts or cardiomyocytes, respectively. Furthermore, we found that the expression levels of Sirt3, mainly located in mitochondria, and its target gene FOXO3a were increased in CD38-deficient hearts and cardiomyocytes with CD38 knockdown under diabetic induction conditions. In conclusion, we demonstrated that CD38 deficiency protected mice from diabetes-induced diabetic cardiomyopathy by reducing pyroptosis and apoptosis via activating NAD+/Sirt3/FOXO3a signaling pathways.

The role of N6-methyladenosine RNA modification in platinum resistance.

N6-methyladenosine (m6A) RNA methylation, a dynamic regulator of transcript expression, plays a pivotal role in cancer by influencing diverse mRNA processes, including nuclear export, splicing, translation and decay. It intersects with cancer biology, impacting progression, treatment sensitivity and prognosis. Platinum-based compounds are essential in cancer treatment, while intrinsic or acquired resistance poses a formidable challenge, limiting therapeutic efficacy. Recent breakthroughs have established a direct association between m6A RNA methylation and platinum resistance in various cancer types. This review summarized related studies, aiming to provide profound insights into the interplay between m6A-associated regulation and platinum-resistance mechanisms in cancer. It explores therapeutic approaches, including personalized treatments based on m6A profiles, guiding future research to enhance clinical strategies for oncological prognostic outcomes.

Cancer poses a global health challenge, with platinum-based drugs as a cornerstone of treatment. Regrettably, cancer cells can develop resistance to these drugs, diminishing their effectiveness. Recent research suggests that a subtle modification known as N⁶-methyladenosine (m6A) on RNA molecules may contribute to this resistance. m6A acts as a minuscule tag on RNA molecules within the cells, akin to a genetic switch. When altered, it can render cancer cells less responsive to platinum-based drugs. Scientists have found that m6A changes in various cancer types can bolster resistance to platinum-based drugs. This reduced drug efficacy presents a significant concern, as platinum-based drugs are vital in treating diverse cancer types, including ovarian, lung and colorectal cancer. Understanding the impact of m6A on platinum resistance is pivotal. It may enable doctors to identify patients less likely to respond to treatment. Researchers are also investigating methods to target m6A alterations in cancer cells, potentially rendering them more receptive to platinum-based drugs. Ongoing research into m6A and its role in platinum resistance holds promise for enhancing cancer treatments, ultimately increasing the chances of success for patients requiring platinum-based drugs.

Proposal of optically tunable and reconfigurable multi-channel bandstop filter using sum-frequency generation in a PPLN waveguide.

A multi-wavelength bandstop filter is proposed and numerically demonstrated using the sum-frequency generation (SFG) process in a waveguide of periodically poled lithium niobate (PPLN). This proposed device achieves channels number reconfigurable, central filtering wavelength of each filtering channel independently tunable and extinction ratios (ERs) equalized via all-optical methods.

CD38 deficiency promotes skeletal muscle and brown adipose tissue energy expenditure through activating NAD+-Sirt1-PGC1α signaling pathway.

Obesity is a metabolic syndrome characterized by abnormal lipid deposition and energy imbalance. CD38 is a single-chain transmembrane glycoprotein widely expressed in a variety of cell types. The roles of skeletal muscle and brown fat in CD38 deficiency under HFD-induced obesity remain unknown. In this study, we established obesity model with HFD and examined the changes in metabolites with metabonomics. Our results showed that CD38 expression was increased in muscle and brown fat after HFD treatment. Moreover, the results of metabonomics showed that CD38 deficiency significantly altered the metabolites in energy metabolism, cofactor generation, and redox homeostasis. Furthermore, CD38 deficiency reduced the expressions of NADPH oxidase 2 and FASN in mRNA level. We found that the expressions of Sirt1, Sirt3, and PGC1α were upregulated in CD38-deficient muscle tissue. In brown fat, the Sirt1-3, cell death inducing DFFA-like effector A, ELOVL3, and Dio2 expressions were increased in CD38-deficient mice. Our results showed the uncoupling protein 1 expression was upregulated. And NAD+ supplementation increased the expression of Sirt1 and PGC1α after palmitic acid treatment. Taken together, our results demonstrated that the protection of CD38 deficiency on HFD-induced obesity was related to the inhibition of oxidative stress and increasing energy expenditure via activating NAD+/Sirtuins signaling pathways in muscle and brown fat.

Effects of lysate/tissue storage at -80°C on subsequently extracted EVs of epithelial ovarian cancer tissue origins.

Small extracellular vesicles (sEVs) and large extracellular vesicles (lEVs), play vital roles in intercellular communication. We optimized a method that extracts EVs from epithelial ovarian cancer (EOC) tissues for the purpose of investigating whether cryopreservation of EOC tissues affects the phenotypes, contents, and biological functions of extracted EVs. EV morphology, the number and size distribution of EVs, and EV-related markers were analyzed. Storage of lysates at -80°C decreased lEV yield and increased sEV yield, whereas storage of tissues at -80°C increased both sEV and lEV yields; neither changed the morphology or particle mass ratio of EVs. The two cryopreservation groups retained over 90% of proteins and 80% of miRNAs detected in the "fresh" group. EVs extracted following lysate/tissue storage at -80°C could also promote angiogenesis and invasive migration ability in human endothelial cells. Cryopreserved EOC tissue may benefit clinical applications for studies of tissue-derived EVs, especially EV proteins-related ones.

Psychobiotic Lactobacillus plantarum JYLP-326 relieves anxiety, depression, and insomnia symptoms in test anxious college via modulating the gut microbiota and its metabolism.

Introduction: Test anxiety is a common issue among college students, which can affect their physical and psychological health. However, effective interventions or therapeutic strategies are still lacking. This study aims to evaluate the potential effects of Lactobacillus plantarum JYLP-326 on test anxious college students. Methods: Sixty anxious students were enrolled and randomly allocated to the placebo group and the probiotic group. Both groups were instructed to take placebo and JYLP-326 products twice per day for three weeks, respectively. Thirty unanxious students with no treatments were assigned to a regular control group. The anxiety, depression, and insomnia questionnaires were used to measure students' mental states at the baseline and the end of this study. 16S rRNA sequencing and untargeted metabolomics were performed to analyze the changes in the gut microbiota and fecal metabolism. Results: The questionnaire results suggested that JYLP-326 administration could relieve the symptoms of anxiety, depression, and insomnia in test anxious students. The gut microbiomes of the placebo group showed a significantly greater diversity index than the control group (p < 0.05). An increased abundance of Bacteroides and Roseburia at the genus level was observed in the placebo group, and the relative abundance of Prevotella and Bifidobacterium decreased. Whereas, JYLP-326 administration could partly restore the disturbed gut microbiota. Additionally, test anxiety was correlated with disordered fecal metabolomics such as a higher Ethyl sulfate and a lower Cyclohexylamine, which could be reversed after taking JYLP-326. Furthermore, the changed microbiota and fecal metabolites were significantly associated with anxiety-related symptoms. Conclusion: The results indicate that the intervention of L. plantarum JYLP-326 could be an effective strategy to alleviate anxiety, depression, and insomnia in test anxious college students. The potential mechanism underlying this effect could be related to the regulation of gut microbiota and fecal metabolites.

Inhibition of invasion and metastasis in choriocarcinoma by migration and invasion inhibitory protein.

INTRODUCTION: Choriocarcinoma is a highly invasive gynaecologic malignancy. Molecular mechanism of metastasis in choriocarcinoma is poorly understood. Migration and invasion inhibitory protein (MIIP) regulates cell migration and invasion. Therefore, we aimed to elucidate the function of MIIP in choriocarcinoma. METHODS: Choriocarcinoma cell lines, JAR and JEG-3, were transfected with lentivirus carrying the MIIP-interfering RNA (to downregulate MIIP expression) or left untransfected (negative control). Cell migration and invasion were studied using transwell migration assays and scratch assays. In vivo tumour burden was studied using tumour xenograft models in specific-pathogen-free nude mice and live imaging. We elucidated possible molecular signalling pathways using western blotting. RESULTS: In transwell migration and scratch assays MIIP-downregulated JAR and JEG-3 cells migrated and invaded faster compared to their respective negative control cells. Migration and invasion by the MIIP-upregulated SWAN cells was slower than that by negative control SWAN cells. Live imaging revealed that bioluminescence values were higher in MIIP-downregulated tumours than in the negative control tumours. Mice with MIIP-downregulated tumours had higher serum human chorionic gonadotropin (HCG) levels than those with negative control tumours. The MIIP expression was negatively correlated with that of histone deacetylase (HDAC6) and positively correlated with that of acetylated α-tubulin. DISCUSSION: Thus, MIIP-by inhibiting cellular motility in choriocarcinoma-acts as a tumour suppressor gene. This highlights a potential therapeutic target for refractory choriocarcinoma. Additionally, HDAC6 and acetylated α-tubulin may be involved in the regulatory effects of MIIP on the biobehaviour of choriocarcinoma cells.

m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress.

Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N6-methyladenosine (m6A) and stabilized by IGF2BP1, a cellular m6A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat-induced m6A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m6A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.

PLAA suppresses ovarian cancer metastasis via METTL3-mediated m6A modification of TRPC3 mRNA.

Wide metastasis contributes to a high death rate in ovarian cancer, and understanding of the molecular mechanism helps to find effective targets for metastatic ovarian cancer therapy. It has been found that phospholipase A2-activating protein (PLAA) is inactivated in some cancers, but its role in cancer metastasis remains unknown. Here, we found that PLAA was significantly downregulated in ovarian cancer highly metastatic cell lines and patients, and the low expression of PLAA was associated with poorer prognosis and high-risk clinicopathological features of patients. PLAA inhibited the migration and invasion of ovarian cancer cells and metastasis of transplanted tumor in the orthotopic xenograft mouse model. Meanwhile, PLAA inhibited metastasis of ovarian cancer by inhibiting transient receptor potential channel canonical 3 (TRPC3)-mediated the intracellular Ca2+ level. Mechanistically, PLAA inhibited methyltransferase-like 3 (METTL3) expression through the ubiquitin-mediated degradation, and METTL3 stabilized TRPC3 mRNA expression via N6-methyladenosine (m6A) modification. Our study verified the function and mechanism of the PLAA-METTL3-TRPC3 axis involved in ovarian cancer metastasis, with a view to providing a potential therapeutic approach for ovarian cancer.

TRIM47 is a novel endothelial activation factor that aggravates lipopolysaccharide-induced acute lung injury in mice via K63-linked ubiquitination of TRAF2.

Endothelial activation plays an essential role in the pathogenesis of sepsis-induced acute lung injury, however, the detailed regulatory mechanisms remain largely unknown. Here, we reported that TRIM47, an E3 ubiquitin ligase of the tripartite motif-containing protein family, was highly expressed in vascular endothelial cells. TRIM47-deficient mice were effectively resistant to lipopolysaccharide (LPS)-induced acute lung injury and death by attenuating pulmonary inflammation. TRIM47 was upregulated during TNFα-induced endothelial activation in vitro. Knockdown of TRIM47 in endothelial cells inhibited the transcription of multiple pro-inflammatory cytokines, reduced monocyte adhesion and the expression of adhesion molecules, and suppressed the secretion of IL-1ß and IL-6 in endothelial cells. By contrast, overexpression of TRIM47 promoted inflammatory response and monocyte adhesion upon TNFα stimulation. In addition, TRIM47 was able to activate the NF-κB and MAPK signaling pathways during endothelial activation. Furthermore, our experiments revealed that TRIM47 resulted in endothelial activation by promoting the K63-linked ubiquitination of TRAF2, a key component of the TNFα signaling pathway. Taken together, our studies demonstrated that TRIM47 as a novel activator of endothelial cells, promoted LPS-induced pulmonary inflammation and acute lung injury through potentiating the K63-linked ubiquitination of TRAF2, which in turn activates NF-κB and MAPK signaling pathways to trigger an inflammatory response in endothelial cells.

CD38 deficiency protects the retina from ischaemia/reperfusion injury partly via suppression of TLR4/MyD88/NF-κB signalling.

PURPOSE: This study aimed to explore cellular localisation of CD38 in the retina and evaluate the role and potential mechanism of CD38 deficiency in retinal ischaemia/reperfusion (I/R) injury. METHODS: Six-to eight-week-old male CD38 knockout (KO) and wild-type mice in C57BL/6 background were used. Immunostaining was performed to determine the cellular localisation of CD38 in the retina. Haematoxylin and eosin staining and immunostaining of Brn3a were used to evaluate the retinal I/R injury. Western blotting was performed to detect toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), p-p65, ionised calcium-binding adapter molecule 1, Sirtuin1 (Sirt1), Ac-p65, and pro-inflammatory cytokines protein expression. RESULTS: CD38 was highly expressed in mouse retinal microglia and astrocytes/Müller cells. CD38 deficiency reduced I/R-induced retinal damage and retinal ganglion cell death. Following retinal I/R injury, TLR4, MyD88, nuclear factor-κB p-p65 (NF-κB p-p65), pro-inflammatory cytokines and CD38 protein levels were also upregulated. After I/R injury, retinal inflammation factors IL-1ß, IL-6, and TNF-α mRNA and protein levels were increased. IL-1ß, IL-6, and TNF-α were reduced in CD38 KO mice after I/R injury. Retinal I/R injury induced the activation of microglia, but this effect was also suppressed by KO of CD38. Additionally, retinal I/R induced a significant increase in Ac-p65 protein levels and decrease in Sirt1 protein levels, while this effect was greatly attenuated by KO of CD38. CONCLUSION: CD38 deficiency protects the retina from I/R injury by suppressing microglial activation partly via activating Sirt1-mediated suppression of TLR4/MyD88/NF-κB signalling.

Mode selection in InGaAs/InGaAsP quantum well photonic crystal lasers based on coupled double-heterostructure cavities.

Photonic crystal lasers with a high-Q factor and small mode volume are ideal light sources for on-chip nano-photonic integration. Due to the submicron size of their active region, it is usually difficult to achieve high output power and single-mode lasing at the same time. In this work, we demonstrate well-selected single-mode lasing in a line-defect photonic crystal cavity by coupling it to the high-Q modes of a short double-heterostructure photonic crystal cavity. One of the FP-like modes of the line-defect cavity can be selected to lase by thermo-optically tuning the high-Q mode of the short cavity into resonance. Six FP-like modes are successively tuned into lasing with side mode suppression ratios all exceeding 15 dB. Furthermore, we show a continuous wavelength tunability of about 10 nm from all the selected modes. The coupled cavity system provides a remarkable platform to explore the rich laser physics through the spatial modulation of vacuum electromagnetic field at submicron scale.

Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers.

RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (m5C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m5C. Gynecologic cancers are malignancies starting from women's reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to m5C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m5C reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent m5C-YBX1-KRT13 oncogenic regulatory pathway.

Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis.

Microbiota-host interactions play critical roles in colorectal cancer (CRC) progression, however, the underlying mechanisms remain elusive. Here, we uncover that Fusobacterium nucleatum (F. nucleatum) induces a dramatic decline of m6A modifications in CRC cells and patient-derived xenograft (PDX) tissues by downregulation of an m6A methyltransferase METTL3, contributing to inducation of CRC aggressiveness. Mechanistically, we characterized forkhead box D3 (FOXD3) as a transcription factor for METTL3. F. nucleatum activates YAP signaling, inhibits FOXD3 expression, and subsequently reduces METTL3 transcription. Downregulation of METTL3 promotes its target kinesin family member 26B (KIF26B) expression by reducing its m6A levels and diminishing YTHDF2-dependent mRNA degradation, which contributes to F. nucleatum-induced CRC metastasis. Moreover, METTL3 expression is negatively correlated with F. nucleatum and KIF26B levels in CRC tissues. A high expression of KIF26B is also significantly correlated with a shorter survival time of CRC patients. Together, our findings provide insights into modulating human m6A epitranscriptome by gut microbiota, and its significance in CRC progression.

Double-Pulse Generation of Indistinguishable Single Photons with Optically Controlled Polarization.

Single-photon sources play a key role in photonic quantum technologies. Semiconductor quantum dots can emit indistinguishable single photons under resonant excitation. However, the resonance fluorescence technique typically requires cross-polarization filtering, which causes a loss of the unpolarized quantum dot emission by 50%. To solve this problem, we demonstrate a method for generating indistinguishable single photons with optically controlled polarization by two laser pulses off-resonant with neutral exciton states. This scheme is realized by exciting the quantum dot to the biexciton state and subsequently driving the quantum dot to an exciton eigenstate. By combining with a magnetic field, we demonstrated the generation of photons with optically controlled polarization (the degree of polarization is 101(2)%), laser-neutral exciton detuning up to 0.81 meV, high single-photon purity (99.6(1)%), and indistinguishability (85(4)%). Laser pulses can be blocked using polarization and spectral filtering. Our work makes an important step toward indistinguishable single-photon sources with near-unity collection efficiency.