Single-cell dissection of cervical cancer reveals key subsets of the tumor immune microenvironment.

The tumor microenvironment (TME) directly determines patients' outcomes and therapeutic efficiencies. An in-depth understanding of the TME is required to improve the prognosis of patients with cervical cancer (CC). This study conducted single-cell RNA and TCR sequencing of six-paired tumors and adjacent normal tissues to map the CC immune landscape. T and NK cells were highly enriched in the tumor area and transitioned from cytotoxic to exhaustion phenotypes. Our analyses suggest that cytotoxic large-clone T cells are critical effectors in the antitumor response. This study also revealed tumor-specific germinal center B cells associated with tertiary lymphoid structures. A high-germinal center B cell proportion in patients with CC is predictive of improved clinical outcomes and is associated with elevated hormonal immune responses. We depicted an immune-excluded stromal landscape and established a joint model of tumor and stromal cells to predict CC patients' prognosis. The study revealed tumor ecosystem subsets linked to antitumor response or prognosis in the TME and provides information for future combinational immunotherapy.

Antibody Profiling of Pan-Cancer Viral Proteome Reveals Biomarkers for Nasopharyngeal Carcinoma Diagnosis and Prognosis.

Diagnosing, predicting disease outcome, and identifying effective treatment targets for virus-related cancers are lacking. Protein biomarkers have the potential to bridge the gap between prevention and treatment for these types of cancers. While it has been shown that certain antibodies against EBV proteins could be used to detect nasopharyngeal carcinoma (NPC), antibodies targeting are solely a tiny part of the about 80 proteins expressed by the EBV genome. Furthermore, it remains unclear what role other viruses play in NPC since many diseases are the result of multiple viral infections. For the first time, this study measured both IgA and IgG antibody responses against 646 viral proteins from 23 viruses in patients with NPC and control subjects using nucleic acid programmable protein arrays. Candidate seromarkers were then validated by ELISA using 1665 serum samples from three clinical cohorts. We demonstrated that the levels of five candidate seromarkers (EBV-BLLF3-IgA, EBV-BLRF2-IgA, EBV-BLRF2-IgG, EBV-BDLF1-IgA, EBV-BDLF1-IgG) in NPC patients were significantly elevated than controls. Additional examination revealed that NPC could be successfully diagnosed by combining the clinical biomarker EBNA1-IgA with the five anti-EBV antibodies. The sensitivity of the six-antibody signature at 95% specificity to diagnose NPC was comparable to the current clinically-approved biomarker combination, VCA-IgA, and EBNA1-IgA. However, the recombinant antigens of the five antibodies are easier to produce and standardize compared to the native viral VCA proteins. This suggests the potential replacement of the traditional VCA-IgA assay with the 5-antibodies combination to screen and diagnose NPC. Additionally, we investigated the prognostic significance of these seromarkers titers in NPC. We showed that NPC patients with elevated BLLF3-IgA and BDLF1-IgA titers in their serum exhibited significantly poorer disease-free survival, suggesting the potential of these two seromarkers as prognostic indicators of NPC. These findings will help develop serological tests to detect and treat NPC in the future.

dSCOPE: a software to detect sequences critical for liquid-liquid phase separation.

Membrane-based cells are the fundamental structural and functional units of organisms, while evidences demonstrate that liquid-liquid phase separation (LLPS) is associated with the formation of membraneless organelles, such as P-bodies, nucleoli and stress granules. Many studies have been undertaken to explore the functions of protein phase separation (PS), but these studies lacked an effective tool to identify the sequence segments that critical for LLPS. In this study, we presented a novel software called dSCOPE (http://dscope.omicsbio.info) to predict the PS-driving regions. To develop the predictor, we curated experimentally identified sequence segments that can drive LLPS from published literature. Then sliding sequence window based physiological, biochemical, structural and coding features were integrated by random forest algorithm to perform prediction. Through rigorous evaluation, dSCOPE was demonstrated to achieve satisfactory performance. Furthermore, large-scale analysis of human proteome based on dSCOPE showed that the predicted PS-driving regions enriched various protein post-translational modifications and cancer mutations, and the proteins which contain predicted PS-driving regions enriched critical cellular signaling pathways. Taken together, dSCOPE precisely predicted the protein sequence segments critical for LLPS, with various helpful information visualized in the webserver to facilitate LLPS-related research.

qPTM: an updated database for PTM dynamics in human, mouse, rat and yeast.

Post-translational modifications (PTMs) are critical molecular mechanisms that regulate protein functions temporally and spatially in various organisms. Since most PTMs are dynamically regulated, quantifying PTM events under different states is crucial for understanding biological processes and diseases. With the rapid development of high-throughput proteomics technologies, massive quantitative PTM proteome datasets have been generated. Thus, a comprehensive one-stop data resource for surfing big data will benefit the community. Here, we updated our previous phosphorylation dynamics database qPhos to the qPTM (http://qptm.omicsbio.info). In qPTM, 11 482 553 quantification events among six types of PTMs, including phosphorylation, acetylation, glycosylation, methylation, SUMOylation and ubiquitylation in four different organisms were collected and integrated, and the matched proteome datasets were included if available. The raw mass spectrometry based false discovery rate control and the recurrences of identifications among datasets were integrated into a scoring system to assess the reliability of the PTM sites. Browse and search functions were improved to facilitate users in swiftly and accurately acquiring specific information. The results page was revised with more abundant annotations, and time-course dynamics data were visualized in trend lines. We expected the qPTM database to be a much more powerful and comprehensive data repository for the PTM research community.

5-methylcytosine modification by Plasmodium NSUN2 stabilizes mRNA and mediates the development of gametocytes.

5-methylcytosine (m5C) is an important epitranscriptomic modification involved in messenger RNA (mRNA) stability and translation efficiency in various biological processes. However, it remains unclear if m5C modification contributes to the dynamic regulation of the transcriptome during the developmental cycles of Plasmodium parasites. Here, we characterize the landscape of m5C mRNA modifications at single nucleotide resolution in the asexual replication stages and gametocyte sexual stages of rodent (Plasmodium yoelii) and human (Plasmodium falciparum) malaria parasites. While different representations of m5C-modified mRNAs are associated with the different stages, the abundance of the m5C marker is strikingly enhanced in the transcriptomes of gametocytes. Our results show that m5C modifications confer stability to the Plasmodium transcripts and that a Plasmodium ortholog of NSUN2 is a major mRNA m5C methyltransferase in malaria parasites. Upon knockout of P. yoelii nsun2 (pynsun2), marked reductions of m5C modification were observed in a panel of gametocytogenesis-associated transcripts. These reductions correlated with impaired gametocyte production in the knockout rodent malaria parasites. Restoration of the nsun2 gene in the knockout parasites rescued the gametocyte production phenotype as well as m5C modification of the gametocytogenesis-associated transcripts. Together with the mRNA m5C profiles for two species of Plasmodium, our findings demonstrate a major role for NSUN2-mediated m5C modifications in mRNA transcript stability and sexual differentiation in malaria parasites.

Cu2+-Dominated Chirality Transfer from Chiral Molecules to Concave Chiral Au Nanoparticles.

Foreign ions as additives are of great significance for realizing excellent control over the morphology of noble metal nanostructures in the state-of-the-art seed-mediated growth method; however, they remain largely unexplored in chiral synthesis. Here, we report on a Cu2+-dominated chiral growth strategy that can direct the growth of concave chiral Au nanoparticles with C3-dominant chiral centers. The introduction of trace amounts of Cu2+ ions in the seed-mediated chiral growth process is found to dominate the chirality transfer from chiral molecules to chiral nanoparticles, leading to the formation of chiral nanoparticles with a concave VC geometry. Both experimental and theoretical results further demonstrate the correlation between the nanoparticle structure and optical chirality for the concave chiral nanoparticle. The Cu2+ ion is found to dominate the chiral growth by selectively activating the deposition of Au atoms along the [110] and [111] directions, facilitating the formation of the concave VC. We further demonstrate that the Cu2+-dominated chiral growth strategy can be employed to generate a variety of concave chiral nanoparticles with enriched geometric chirality and desired chiroptical properties. Concave chiral nanoparticles also exhibit appealing catalytic activity and selectivity toward electrocatalytic oxidation of enantiomers in comparison to helicoidal nanoparticles. The ability to tune the geometric chirality in a controlled manner by simply manipulating the Cu2+ ions as additives opens up a promising strategy for creating chiral nanomaterials with increasing architectural diversity for chirality-dependent optical and catalytic applications.

Chiral Au-Pd Alloy Nanorods with Tunable Optical Chirality and Catalytically Active Surfaces.

Integrating the plasmonic chirality with excellent catalytic activities in plasmonic hybrid nanostructures provides a promising strategy to realize the chiral nanocatalysis toward many chemical reactions. However, the controllable synthesis of catalytically active chiral plasmonic nanoparticles with tailored geometries and compositions remains a significant challenge. Here it is demonstrated that chiral Au-Pd alloy nanorods with tunable optical chirality and catalytically active surfaces can be achieved by a seed-mediated coreduction growth method. Through manipulating the chiral inducers, Au nanorods selectively transform into two different intrinsically chiral Au-Pd alloy nanorods with distinct geometric chirality and tunable optical chirality. By further adjusting several key synthetic parameters, the optical chirality, composition, and geometry of the chiral Au-Pd nanorods are fine-tailored. More importantly, the chiral Au-Pd alloy nanorods exhibit appealing chiral catalytic activities as well as polarization-dependent plasmon-enhanced nanozyme catalytic activity, which has great potential for chiral nanocatalysis and plasmon-induced chiral photochemistry.

Controllable nonreciprocal phonon laser in a hybrid photonic molecule based on directional quantum squeezing.

Here, a scheme for a controllable nonreciprocal phonon laser is proposed in a hybrid photonic molecule system consisting of a whispering-gallery mode (WGM) optomechanical resonator and a χ(2)-nonlinear WGM resonator, by directionally quantum squeezing one of two coupled resonator modes. The directional quantum squeezing results in a chiral photon interaction between the resonators and a frequency shift of the squeezed resonator mode with respect to the unsqueezed bare mode. We show that the directional quantum squeezing can modify the effective optomechanical coupling in the optomechanical resonator, and analyze the impacts of driving direction and squeezing extent on the phonon laser action in detail. Our analytical and numerical results indicate that the controllable nonreciprocal phonon laser action can be effectively realized in this system. The proposed scheme uses an all-optical and chip-compatible approach without spinning resonators, which may be more beneficial for integrating and packaging of the system on a chip. Our proposal may provide a new route to realize integratable phonon devices for on-chip nonreciprocal phonon manipulations, which may be used in chiral quantum acoustics, topological phononics, and acoustical information processing.

Clinical courses and outcomes of COVID-19 associated pulmonary aspergillosis in 168 patients with the SARS-CoV-2 omicron variant.

PURPOSE: We aimed to analyze the clinical features of COVID-19-associated pulmonary aspergillosis (CAPA) during the SARS-CoV-2 Omicron variant pandemic and to reveal the risk factors for CAPA and death. METHODS: A retrospective cohort study was conducted on 168 CAPA patients from December 8, 2022 to January 31, 2023. 168 COVID-19 patients without secondary fungal infection during this period were matched 1:1 using propensity score matching as controls. RESULTS: The incidence of CAPA was 3.8% (168/4421). Compared with patients without fungal infection, CAPA patients had a higher mortality (43.5% vs. 10.1%, P < 0.001). Patients in the death group (n = 73) were more likely to be admitted to ICU (91.8% vs. 26.3%, p < 0.001), had a shorter ICU length of hospitalization (10 (IQR, 6 ~ 16.5) days vs. 14 (IQR, 8 ~ 37) days, p = 0.012). Immunocompromised status (p = 0.023), NLR ≥ 5.7 (p = 0.004), CRP ≥ 50 mg/L (p = 0.043), and the number of antibiotics ≥ 3 (p < 0.001) were all risk factors for CAPA; NLR ≥ 5.7 (p = 0.009) and the number of antibiotics ≥ 3 (p = 0.018) were all independent risk factors for death. CONCLUSIONS: During the Omicron variant pandemic, CAPA increased death and ICU length of hospitalization. The risk factors of CAPA and death obtained from the study can help us further understand the disease characteristics of CAPA and better guide our clinical decision-making.

qPTMplants: an integrative database of quantitative post-translational modifications in plants.

As a crucial molecular mechanism, post-translational modifications (PTMs) play critical roles in a wide range of biological processes in plants. Recent advances in mass spectrometry-based proteomic technologies have greatly accelerated the profiling and quantification of plant PTM events. Although several databases have been constructed to store plant PTM data, a resource including more plant species and more PTM types with quantitative dynamics still remains to be developed. In this paper, we present an integrative database of quantitative PTMs in plants named qPTMplants (http://qptmplants.omicsbio.info), which hosts 1 242 365 experimentally identified PTM events for 429 821 nonredundant sites on 123 551 proteins under 583 conditions for 23 PTM types in 43 plant species from 293 published studies, with 620 509 quantification events for 136 700 PTM sites on 55 361 proteins under 354 conditions. Moreover, the experimental details, such as conditions, samples, instruments and methods, were manually curated, while a variety of annotations, including the sequence and structural characteristics, were integrated into qPTMplants. Then, various search and browse functions were implemented to access the qPTMplants data in a user-friendly manner. Overall, we anticipate that the qPTMplants database will be a valuable resource for further research on PTMs in plants.

Genome-wide landscape of ApiAP2 transcription factors reveals a heterochromatin-associated regulatory network during Plasmodium falciparum blood-stage development.

Heterochromatin-associated gene silencing controls multiple physiological processes in malaria parasites, however, little is known concerning the regulatory network and cis-acting sequences involved in the organization of heterochromatin and how they modulate heterochromatic gene expression. Based on systematic profiling of genome-wide occupancy of eighteen Apicomplexan AP2 transcription factors by ChIP-seq analysis, we identify and characterize eight heterochromatin-associated factors (PfAP2-HFs), which exhibit preferential enrichment within heterochromatic regions but with differential coverage profiles. Although these ApiAP2s target euchromatic gene loci via specific DNA motifs, they are likely integral components of heterochromatin independent of DNA motif recognition. Systematic knockout screenings of ApiAP2 factors coupled with RNA-seq transcriptomic profiling revealed three activators and three repressors of heterochromatic gene expression including four PfAP2-HFs. Notably, expression of virulence genes is either completely silenced or significantly reduced upon the depletion of PfAP2-HC. Integrated multi-omics analyses reveal autoregulation and feed-forward loops to be common features of the ApiAP2 regulatory network, in addition to the occurrence of dynamic interplay between local chromatin structure and ApiAP2s in transcriptional control. Collectively, this study provides a valuable resource describing the genome-wide landscape of the ApiAP2 family and insights into functional divergence and cooperation within this family during the blood-stage development of malaria parasites.

Comparison of the clinical characteristics in parents and their children in a series of family clustered Mycoplasma pneumoniae infections.

BACKGROUND: Mycoplasma pneumoniae infections have increased in China recently, causing some evidence of familial clustering. The purpose of this study was to compare the clinical features of parents and children in cases of familial clustering of Mycoplasma pneumoniae infection. METHODS: A retrospective analysis was performed on the cases of familial clustering of Mycoplasma pneumoniae infection, and the clinical characteristics of parents and children were compared. RESULTS: We identified 63 families, of these, 57 (65.5%) adults and 65 (94.2%) children required hospitalization. Fifty-seven adults (mean age 35.1 ± 4.6 years, 80.7% female) and 55 children (mean age 6.3 ± 3.9 years, 54.5% female) were included in the analysis. The incidence of mycoplasma infection in adults had increased gradually over the past year, while the rate in children had spiked sharply since June 2023. The clinical symptoms were similar in the two groups, mainly fever and cough. The peak temperature of children was higher than that of adults (39.1 ± 0.7℃ vs 38.6 ± 0.7℃, p = 0.004). Elevated lactate dehydrogenase was more common in children than in adults (77.8% vs 11.3%, p < 0.001). Bronchial pneumonia and bilateral involvement were more common in children, while adults usually had unilateral involvement. Three (60%) adults and 21 (52.5%) children were macrolide-resistant Mycoplasma pneumoniae infected. Children were more likely to be co-infected (65.5% vs 22.8%, p < .001). Macrolides were used in most children and quinolones were used in most adults. Ten (18.2%) children were diagnosed with severe Mycoplasma pneumoniae pneumonia, whereas all adults had mild disease. Children had a significantly longer fever duration than adults ((5.6 ± 2.2) days vs (4.1 ± 2.2) days, p = 0.002). No patient required mechanical ventilation or died. CONCLUSIONS: Mycoplasma pneumoniae infection shows a familial clustering epidemic trend at the turn of summer and autumn, with different clinical characteristics between parents and children.

Tuning the Plexcitonic Optical Chirality Using Discrete Structurally Chiral Plasmonic Nanoparticles.

Constructing chiral plexcitonic systems with tunable plasmon-exciton coupling may advance the scientific exploitation of strong light-matter interactions. Because of their intriguing chiroptical properties, chiral plasmonic materials have shown promising applications in photonics, sensing, and biomedicine. However, the strong coupling of chiral plasmonic nanoparticles with excitons remains largely unexplored. Here we demonstrate the construction of a chiral plasmon-exciton system using chiral AuAg nanorods and J aggregates for tuning the plexcitonic optical chirality. Circular dichroism spectroscopy was employed to characterize chiral plasmon-exciton coupling, in which Rabi splitting and anticrossing behaviors were observed, whereas the extinction spectra exhibited less prominent phenomena. By controlling the number of molecular excitons and the energy detuning between plasmons and excitons, we have been able to fine-tune the plexcitonic optical chirality. The ability to fine-tune the plexcitonic optical chirality opens up unique opportunities for exploring chiral light-matter interactions and boosting the development of emerging chiroptical devices.

Randomised, controlled crossover trial of intermittent and continuous transcutaneous electrical stimulation of the genioglossus muscle for obstructive sleep apnoea.

PURPOSE: Continuous transcutaneous electrical stimulation (CTES) of the genioglossus muscle may benefit patients with obstructive sleep apnoea (OSA). However, the therapeutic value of intermittent transcutaneous electrical stimulation (ITES) for OSA is unclear. METHODS: This was a randomised, controlled, crossover study to compare the effects of ITES and CTES of the genioglossus muscle. Over three single-night sessions, participants were alternately subjected to three genioglossus stimulation modalities during sleep (sham, CTES and ITES). The apnoea-hypopnoea index (AHI) and oxygen desaturation index (ODI) were used for OSA diagnosis and to evaluate efficacy. A responder was defined as an individual with a ≥50% reduction in AHI together with <10 AHI events per hour and/or an ODI reduction of ≥25% between sham stimulation and electrical stimulation nights. RESULTS: Fifteen men with OSA completed the study. Compared with sham, the median AHI with ITES decreased by 13.3 events/hour (95% CI 3.1 to 23.5, p=0.030) and by 7.3 events/hour (95% CI -3.9 to 18.5, p=0.825) with CTES. The median ODI was reduced by 9.25 events/hour (95% CI 0.5 to 18.0) with ITES and 3.3 events/hour (95% CI -5.6 to 12.2) with CTES; however, there was no significant difference between groups. Furthermore, ITES outperformed CTES with respect to longest apnoea duration (median (95% CI), 9.5 (0.0 to 19.0), p=0.011)) and the highest sleep efficiency (12.2 (2.7 to 21.7), p=0.009). Of the 15 participants, 8 responded to ITES and 3 responded to CTES (p=0.058), of whom all eight cases and two out of three cases had ODIs <5 events/hour, respectively. All participants tolerated ITES well. CONCLUSIONS: ITES improved upper airway obstruction in patients with OSA, suggesting that further prospective validation of the intermittent approach is warranted. TRIAL REGISTRATION NUMBER: ChiCTR2100050138.

Site-Selective Chiral Growth of Anisotropic Au Triangular Nanoplates for Tuning the Optical Chirality.

Site-selective chiral growth of anisotropic nanoparticles is of great importance to realize the plasmonic nanostructures with delicate geometry and desired optical chirality; however, it remains largely unexplored. This work demonstrates a controlled site-selective chiral growth system based on the seed-mediated growth of anisotropic Au triangular nanoplates. The site-selective chiral growth involves two distinct underlying pathways, faceted growth and island growth, which are interswitchable upon maneuvering the interplay of chiral molecules, surfactants, and reducing agents. The pathway switch governs the geometric and chirality evolution of Au triangular nanoplates, giving rise to tailorable circular dichroism spectra. The ability to tune the optical chirality in a controlled manner by manipulating the site-selective chiral growth pathway opens up a promising strategy for exploiting chiral metamaterials with increasing architectural complexity in chiroptical applications.

iCysMod: an integrative database for protein cysteine modifications in eukaryotes.

As important post-translational modifications, protein cysteine modifications (PCMs) occurring at cysteine thiol group play critical roles in the regulation of various biological processes in eukaryotes. Due to the rapid advancement of high-throughput proteomics technologies, a large number of PCM events have been identified but remain to be curated. Thus, an integrated resource of eukaryotic PCMs will be useful for the research community. In this work, we developed an integrative database for protein cysteine modifications in eukaryotes (iCysMod), which curated and hosted 108 030 PCM events for 85 747 experimentally identified sites on 31 483 proteins from 48 eukaryotes for 8 types of PCMs, including oxidation, S-nitrosylation (-SNO), S-glutathionylation (-SSG), disulfide formation (-SSR), S-sulfhydration (-SSH), S-sulfenylation (-SOH), S-sulfinylation (-SO2H) and S-palmitoylation (-S-palm). Then, browse and search options were provided for accessing the dataset, while various detailed information about the PCM events was well organized for visualization. With human dataset in iCysMod, the sequence features around the cysteine modification sites for each PCM type were analyzed, and the results indicated that various types of PCMs presented distinct sequence recognition preferences. Moreover, different PCMs can crosstalk with each other to synergistically orchestrate specific biological processes, and 37 841 PCM events involved in 119 types of PCM co-occurrences at the same cysteine residues were finally obtained. Taken together, we anticipate that the database of iCysMod would provide a useful resource for eukaryotic PCMs to facilitate related researches, while the online service is freely available at http://icysmod.omicsbio.info.

gutMEGA: a database of the human gut MEtaGenome Atlas.

The gut microbiota plays important roles in human health through regulating both physiological homeostasis and disease emergence. The accumulation of metagenomic sequencing studies enables us to better understand the temporal and spatial variations of the gut microbiota under different physiological and pathological conditions. However, it is inconvenient for scientists to query and retrieve published data; thus, a comprehensive resource for the quantitative gut metagenome is urgently needed. In this study, we developed gut MEtaGenome Atlas (gutMEGA), a well-annotated comprehensive database, to curate and host published quantitative gut microbiota datasets from Homo sapiens. By carefully curating the gut microbiota composition, phenotypes and experimental information, gutMEGA finally integrated 59 132 quantification events for 6457 taxa at seven different levels (kingdom, phylum, class, order, family, genus and species) under 776 conditions. Moreover, with various browsing and search functions, gutMEGA provides a fast and simple way for users to obtain the relative abundances of intestinal microbes among phenotypes. Overall, gutMEGA is a convenient and comprehensive resource for gut metagenome research, which can be freely accessed at http://gutmega.omicsbio.info.

DrugCVar: a platform for evidence-based drug annotation for genetic variants in cancer.

MOTIVATION: Targeted therapy for cancer-related genetic variants is critical for precision medicine. Although several databases including The Clinical Interpretation of Variants in Cancer (CIViC), The Oncology Knowledge Base (OncoKB), The Cancer Genome Interpreter (CGI) and My Cancer Genome (MCG) provide clinical interpretations of variants in cancer, the clinical evidence was limited and miscellaneous. In this study, we developed the DrugCVar database, which integrated our manually curated cancer variant-drug targeting evidence from literature and the interpretations from the public resources. RESULTS: In total, 7830 clinical evidences for cancer variant-drug targeting were integrated and classified into 10 evidence tiers. Searching and browsing functions were provided for quick queries of cancer variant-drug targeting evidence. Also, batch annotation module was developed for user-provided massive genetic variants in various formats. Details, such as the mutation function, location of the variants in gene and protein structures and mutation statistics of queried genes in various tumor types, were also provided for further investigations. Thus, DrugCVar could serve as a comprehensive annotation tool to interpret potential drugs for cancer variants especially the massive ones from clinical cancer genomics studies. AVAILABILITY AND IMPLEMENTATION: The database is available at http://drugcvar.omicsbio.info. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The activation of mTOR signalling modulates DNA methylation by enhancing DNMT1 translation in hepatocellular carcinoma.

BACKGROUND: Both dysregulation of mechanistic target of rapamycin (mTOR) signalling and DNA methylation patterns have been shown to be closely associated with tumor progression and serve as promising targets for hepatocellular carcinoma (HCC) therapy. Although their respective roles in HCC have been extensively revealed, the existence of molecular interactions between them remains largely unknown. METHODS: The association of DNA methylation and mTOR signalling in HCC tissues and cell lines was assessed. A Kaplan‒Meier analysis was applied to estimate the overall survival (OS) and recurrence-free survival (RFS) of HCC patients. The modulation of DNMT1 by mTOR in HCC cell lines was determined. The effect of the drug combination in cell lines and mouse models was examined. RESULTS: The results showed that the DNA methylation level was positively associated with the activation of mTOR signalling in HCC tissues and cell lines. Moreover, HCC patients with higher DNA methylation levels and enhanced activation of mTOR signalling exhibited the worst prognosis. Then, we screened methylation-related enzymes and found that the activation of mTOR signalling increased DNMT1 expression and activity. In addition, mTOR enhanced the translational efficiency of DNMT1 in a 4E-BP1-dependent manner, which is based on the pyrimidine rich translational element (PRTE)-containing 5'UTR of DNMT1. Moreover, we demonstrated that the combined inhibition of mTOR and DNMT synergistically inhibited HCC growth in vitro and in vivo. CONCLUSIONS: In addition to some already identified pro-cancer downstream molecules, the activation of mTOR signalling was found to promote DNA methylation by increasing the translation of DNMT1. Furthermore, combined targeting of mTOR and DNMT1 has been demonstrated to have a more effective tumor suppressive function in HCC.

High-speed ADC based on photonic time-stretched technology with dispersion-tunable CFBG.

We propose a photonic time-stretched analog-to-digital converter (PTS-ADC) based on dispersion-tunable chirped fiber Bragg grating (CFBG), by demonstrating a economical ADC system with seven different stretch factors. The stretch factors are tunable by changing the dispersion of CFBG, in order to obtain different sampling points. Accordingly, the total sampling rate of the system can be improved. Only a single channel is required to increase the sampling rate and achieve the effect of multi-channel sampling. Finally, seven groups of different stretch factors ranging from 1.882 to 2.206 are obtained, which are equivalent to seven groups of different sampling points. We successfully recover the input radio frequency (RF) signals with frequencies from 2 GHz to 10 GHz. In addition, the sampling points are increased by 14.4 times and the equivalent sampling rate is increased to 288 GSa/s. The proposed scheme is suitable for commercial microwave radar systems, which can obtain a much higher sampling rate at a low cost.