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This paper reports a transceiver module with a high polarization extinction ratio (PER) for the polarization-maintaining interferometric fiber optic gyroscope (PM-IFOG). This transceiver utilizes a graded-index lens featuring a slanted face coated with a multilayer film, enabling simultaneous collimation and beam splitting. Configurations of the graded-index splitter lens and the corresponding transceiver module are simulated and designed using the ray matrix method and physical optical propagation. The optical loss of the transceiver module is about 3.77 dB, and the PER exceeds 25 dB. The IFOG prototype is implemented by integrating the transceiver module with a PM sensing coil. The bias instability of the IFOG prototype is evaluated to be 0.51°/h by Allan variance. This research contributes to the reduction in size, weight, power consumption, and cost of PM-IFOG systems.
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Surface proteins of Staphylococcus aureus play vital roles in bacterial physiology and pathogenesis. Recent work suggests that surface proteins are spatially regulated by a YSIRK/GXXS signal peptide that promotes cross-wall targeting at the mid-cell, though the mechanisms remain unclear. We previously showed that protein A (SpA), a YSIRK/GXXS protein and key staphylococcal virulence factor, mis-localizes in a ltaS mutant deficient in lipoteichoic acid (LTA) production. Here, we identified that SpA contains another cross-wall targeting signal, the LysM domain, which, in addition to the YSIRK/GXXS signal peptide, significantly enhances SpA cross-wall targeting. We show that LTA synthesis, but not LtaS, is required for SpA septal anchoring and cross-wall deposition. Interestingly, LTA is predominantly found at the peripheral cell membrane and is diminished at the septum of dividing staphylococcal cells, suggesting a restriction mechanism for SpA septal localization. Finally, we show that D-alanylation of LTA abolishes SpA cross-wall deposition by disrupting SpA distribution in the peptidoglycan layer without altering SpA septal anchoring. Our study reveals that multiple factors contribute to the spatial regulation and cross-wall targeting of SpA via different mechanisms, which coordinately ensures efficient incorporation of surface proteins into the growing peptidoglycan during the cell cycle.
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Lipopolissacarídeos/biossíntese , Peptidoglicano/biossíntese , Sinais Direcionadores de Proteínas/fisiologia , Proteína Estafilocócica A/metabolismo , Staphylococcus aureus/metabolismo , Ácidos Teicoicos/biossíntese , Ciclo Celular/fisiologia , Membrana Celular/metabolismo , Parede Celular/metabolismo , Proteínas de Membrana/metabolismo , Domínios ProteicosRESUMO
Directly modulated vector beam lasers are increasingly desirable for wide applications ranging from optical manipulation to optical communications. We report the first, to our knowledge, high-speed directly modulated vector beam laser with azimuthally polarized emission. It is a microcylinder cavity interacted with a proper second-order grating on top, which enables single mode lasing and efficient surface emission. Through theoretical and numerical analysis, the laser is designed in detail. With an optimized top grating, the emission of the laser is an azimuthally polarized vector beam. With high-differential-gain material and a small active region, the laser can be directly modulated with a high 3 dB bandwidth reach of 40 GHz in simulation. The proposed high-speed directly modulated semiconductor laser with an azimuthally polarized vector beam is promising for applications in fiber space communications or quantum information.
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BACKGROUND: The present study aimed to develop a novel protein-repellent and antibacterial polymethyl methacrylate (PMMA) dental resin with 2-methacryloyloxyethyl phosphorylcholine (MPC) and quaternary ammonium dimethylaminohexadecyl methacrylate (DMAHDM), and to investigate the effects of water-aging for 6 months on the mechanical properties, protein adsorption, and antibacterial activity of the dental resin. METHODS: Four groups were tested: PMMA control; PMMA + 3% MPC; PMMA + 1.5% DMAHDM; and PMMA + 3% MPC + 1.5% DMADDM in acrylic resin powder. Specimens were water-aged for 1 d, 3 months, and 6 months at 37 â. Their mechanical properties were then measured using a three-point flexure test. Protein adsorption was measured using a micro bicinchoninic acid (BCA) method. A human saliva microcosm model was used to inoculate bacteria on water-aged specimens and to investigate the live/dead staining, metabolic activity of biofilms, and colony-forming units (CFUs). RESULTS: The flexural strength and elastic modulus showed a significant loss after 6 months of water-ageing for the PMMA control (mean ± SD; n = 10); in contrast, the new protein repellent and antibacterial PMMA resin showed no strength loss. The PMMA-MPC-DMAHDM-containing resin imparted a strong antibacterial effect by greatly reducing biofilm viability and metabolic activity. The biofilm CFU count was reduced by about two orders of magnitude (p < 0.05) compared with that of the PMMA resin control. The protein adsorption was 20% that of a commercial composite (p < 0.05). Furthermore, the PMMA-MPC-DMAHDM-containing resin exhibited a long-term antibacterial performance, with no significant difference between 1 d, 3 months and 6 months (p > 0.05). CONCLUSIONS: The flexural strength and elastic modulus of the PMMA-MPC-DMAHDM-containing resin were superior to those of the PMMA control after 6 months of water-ageing. The novel PMMA resin incorporating MPC and DMAHDM exhibited potent and lasting protein-repellent and antibacterial properties.
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Polimetil Metacrilato , Água , Humanos , Antibacterianos/farmacologia , Biofilmes , Metacrilatos/farmacologia , Metilaminas/farmacologia , Polimetil Metacrilato/farmacologia , Proteínas , Água/farmacologia , Fatores de TempoRESUMO
A simple approach to estimating microwave Doppler frequency shift (DFS) based on a single dual-polarization quadrature phase shift keying (DP-QPSK) modulator is proposed and experimentally demonstrated. The scheme is capable of estimating both the value and direction of the DFS simultaneously and precisely owing to the introduction of the reference signal. In the proposed approach, the transmitted signal (microwave carrier) and the reference signal are loaded on the upper branch of the DP-QPSK modulator to generate carrier suppression double-sideband signals, respectively, while the echo signal is loaded on the lower branch of the DP-QPSK modulator to perform carrier suppression single-sideband modulation. Then optical sidebands of two branches are combined and sent to a low-speed photodetector to heterodyne. The value of the DFS is equivalent to the frequency of the beat signal between the transmitted and reference signals; meanwhile, the direction can be distinguished by comparing the frequency of the beat signal between the transmitted and reference signals with the frequency of the beat signal between the echo and reference signals. In the experiment, the accurate measurement of DFSs from $ - {100}\;{\rm kHz}$-100kHz to $ + {100}\;{\rm kHz}$+100kHz at the carrier frequencies of 15, 20, 35, and 39 GHz is implemented with errors less than $ \pm {10}\;{\rm Hz}$±10Hz.
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Glioma treatment using targeted chemotherapy is still far from satisfactory due to not only the limited accumulation but also the multiple survival mechanisms of glioma cells, including up-regulation of both autophagy and programmed cell death ligand 1 (PD-L1) expression. Herein, we proposed a combined therapeutic regimen based on functional gold nanoparticles (AuNPs)-enabled chemotherapy, autophagy inhibition, and blockade of PD-L1 immune checkpoint. Specifically, the legumain-responsive AuNPs (D&H-A-A&C) could passively target the glioma site and form in situ aggregates in response to legumain, leading to enhanced accumulation of doxorubicin (DOX) and hydroxychloroquine (HCQ) at the glioma site. HCQ could inhibit the DOX-induced cytoprotective autophagy and thus resensitize glioma cells to DOX. Parallelly, inhibiting autophagy could also inhibit the formation of autophagy-related vasculogenic mimicry (VM) by glioma stem cells. In vivo studies demonstrated that D&H-A-A&C possessed promising antiglioma effect. Moreover, cotreatment with anti-PD-L1 antibody was able to neutralize immunosuppressed glioma microenvironment and thus unleash antiglioma immune response. In vivo studies showed D&H-A-A&C plus anti-PD-L1 antibody could further enhance antiglioma effect and efficiently prevent recurrence. The effectiveness of this strategy presents a potential avenue to develop a more effective and more personalized combination therapeutic regimen for glioma patients.
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Analgésicos/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Nanopartículas/uso terapêutico , Animais , Anticorpos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Dimerização , Doxorrubicina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ouro/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , CamundongosRESUMO
Based on the transverse electric (TE)/transverse magnetic (TM) polarization diversity in plasmonic Bragg gratings, a compact TM-pass/TE-stop polarizer is theoretically proposed on thin-film lithium niobate on insulator (LNOI) platforms. By introducing a large misalignment between metal gratings on both sides of the LNOI waveguide, we demonstrate a polarizer with a high extinction ratio of 20 dB, a low insertion loss of 2.5 dB, a wide waveband from 1.48 to 1.62 µm, and a compact size of only 23 µm on simulation.
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All Staphylococcus aureus genomes contain a genomic island, which is termed νSaα and characterized by two clusters of tandem repeat sequences, i.e. the exotoxin (set) and 'lipoprotein-like' genes (lpl). Based on their structural similarities the νSaα islands have been classified as type I to IV. The genomes of highly pathogenic and particularly epidemic S. aureus strains (USA300, N315, Mu50, NCTC8325, Newman, COL, JH1 or JH9) belonging to the clonal complexes CC5 and CC8 bear a type I νSaα island. Since the contribution of the lpl gene cluster encoded in the νSaα island to virulence is unclear to date, we deleted the entire lpl gene cluster in S. aureus USA300. The results showed that the mutant was deficient in the stimulation of pro-inflammatory cytokines in human monocytes, macrophages and keratinocytes. Purified lipoprotein Lpl1 was further shown to elicit a TLR2-dependent response. Furthermore, heterologous expression of the USA300 lpl cluster in other S. aureus strains enhanced their immune stimulatory activity. Most importantly, the lpl cluster contributed to invasion of S. aureus into human keratinocytes and mouse skin and the non-invasive S. carnosus expressing the lpl gene cluster became invasive. Additionally, in a murine kidney abscess model the bacterial burden in the kidneys was higher in wild type than in mutant mice. In this infection model the lpl cluster, thus, contributes to virulence. The present report is one of the first studies addressing the role of the νSaα encoded lpl gene cluster in staphylococcal virulence. The finding that the lpl gene cluster contributes to internalization into non-professional antigen presenting cells such as keratinocytes highlights the lpl as a new cell surface component that triggers host cell invasion by S. aureus. Increased invasion in murine skin and an increased bacterial burden in a murine kidney abscess model suggest that the lpl gene cluster serves as an important virulence factor.
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Ilhas Genômicas/genética , Infecções Estafilocócicas/genética , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Virulência/genética , Animais , Células Cultivadas , DNA Bacteriano/genética , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Fatores de Virulência/genéticaRESUMO
Abnormal tumor vessels impede the transport and distribution of chemotherapeutics, resulting in low drug concentration at tumor sites and compromised drug efficacy. Normalizing tumor vessels can modulate tumor vascular permeability, alleviate tumor hypoxia, increase blood perfusion, attenuate interstitial fluid pressure, and improve drug delivery. Herein, a novel strategy combining cediranib, a tumor vessel normalizing agent, with an enzyme responsive size-changeable gold nanoparticle (AuNPs-A&C) was developed. In vivo photoacoustic and fluorescence imaging showed that oral pretreatment with 6 mg/kg/day of cediranib for two consecutive days significantly enhanced the retention of AuNPs-A&C in 4T1 tumor. In vivo photoacoustic imaging for hemoglobin (Hb) and oxyhemoglobin (HbO2), Evans blue assay, and immunofluorescence assay showed that cediranib pretreatment markedly increased tumor vascular permeability and tumor oxygenation, while distinctly decreased the tumor microvessel density, demonstrating normalized tumor vessels and favorably altered microenvironment. Additionally, the combination strategy considerably elevated the tumor targeting capacity of different nanoparticle formulations (AuNPs-PEG, AuNPs-A&C), while coadministration of cediranib and AuNPs-A&C achieved prevailing tumor targeting and antitumor efficacy in 4T1 tumor bearing mouse model. In conclusion, we report a novel combined administration strategy to further improve tumor diagnosis and treatment.
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Antineoplásicos/farmacologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Mama/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Mama/irrigação sanguínea , Mama/efeitos dos fármacos , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Ouro/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos BALB C , Imagem Óptica/métodos , Permeabilidade , Técnicas Fotoacústicas/métodos , Quinazolinas/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Excretion of cytoplasmic proteins (ECP) is a common physiological feature in bacteria and eukaryotes. However, how these proteins without a typical signal peptide are excreted in bacteria is poorly understood. We studied the excretion pattern of cytoplasmic proteins using two glycolytic model enzymes, aldolase and enolase, and show that their excretion takes place mainly during the exponential growth phase in Staphylococcus aureus very similar to that of Sbi, an IgG-binding protein, which is secreted via the Sec-pathway. The amount of excreted enolase is substantial and is comparable with that of Sbi. For localization of the exit site, we fused aldolase and enolase with the peptidoglycan-binding motif, LysM, to trap the enzymes at the cell wall. With both immune fluorescence labeling and immunogold localization on electron microscopic thin sections aldolase and enolase were found apart from the cytoplasmic area particularly in the cross wall and at the septal cleft of dividing cells, whereas the non-excreted Ndh2, a soluble NADH:quinone oxidoreductase, is only seen attached to the inner side of the cytoplasmic membrane. The selectivity, the timing and the localization suggest that ECP is not a result of unspecific cell lysis but is mediated by an as yet unknown mechanism.
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Membrana Celular/metabolismo , Staphylococcus aureus/metabolismo , Proteínas de Bactérias/metabolismo , Transporte Biológico , Parede Celular/metabolismo , Frutose-Bifosfato Aldolase/metabolismo , Fosfopiruvato Hidratase/metabolismo , Ligação ProteicaRESUMO
Excretion of cytosolic proteins (ECP) has been reported in bacteria and eukaryotes. As none of the classical signal peptide (SP) dependent or SP-independent pathways could be associated with ECP, it has been also referred to as 'non-classical protein export'. When microbiologists first began to study this subject in 1990, mainly singular cytoplasmic proteins were investigated, such as GAPDH at the cell surface and in the supernatant of pathogenic streptococci or glutamine synthetase (GlnA) as a major extracellular protein in pathogenic mycobacteria. Later, with the rising popularity of proteomics, it became obvious that the secretome of most bacteria contained a copious amount of cytosolic proteins. In particular ancient proteins such as glycolytic enzymes, chaperones, translation factors or enzymes involved in detoxification of reactive oxygen were found in the supernatants. As the excreted proteins do not possess a common motive, the most widespread opinion is that ECP is due to cell lysis. Indeed, upregulation of autolysins or distortion of the murein structure increased ECP, suggesting that enhanced ECP is some sort of survival strategy to counteract osmotic stress. However, in the meantime there are mounting evidences and hints that speak against cell lysis as a primary mechanism for ECP. Very likely, ECP belongs to the normal life cycle of bacteria and involves a programmed process. This review provides a brief overview of the 'non-classical protein export'.
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Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Bacteriólise , Transporte ProteicoRESUMO
Bacterial adhesion on implants is a first step in the development of chronic foreign body associated infections. Finding strategies to minimize bacterial adhesion may contribute to minimize such infections. It is known that surfaces with oligo-ethylene-glycol (EG3OMe) or poly-ethylene-glycol (PEG2k) terminations decrease unspecific protein adsorption and bacterial adhesion. However, little is known about the influence of serum and its components on bacterial adhesion. We therefore prepared two coatings on gold surface with HS-(CH2)11EG3OMe (EG3OMe) and PEG2k-thiol and studied the role of bovine serum albumin (BSA), γ-globulins, and serum on Staphylococcus aureus adhesion. While BSA and lysozyme showed no adherence even when applied at very high concentrations (100 mg/ml), γ-globulins adsorbed already from 10 mg/ml on. The adsorption of γ-globulins was, however, significantly decreased when it was mixed with BSA in a ratio of 3:1, as it is in the serum. Pretreatment of EG3OMe and PEG2k coatings with γ-globulins or serum strongly promoted adherence of S. aureus when resuspended in buffer, suggesting that γ-globulins play a pivotal role in promoting S. aureus adhesion by its IgG binding proteins; the finding that a spa-deletion mutant, lacking the IgG binding protein A, showed decreased adherence corroborated this. Similarly, when S. aureus was pretreated with serum or γ-globulins its adherence was also significantly decreased. Our findings show that particularly γ-globulins bind to the coated surfaces thus mediating adherence of S. aureus via its protein A. As pretreatment of S. aureus with serum or γ-globulins significantly decreased adherence, treatment of patients with γ-globulins before implant surgery might lower the risk of implant-associated infections.
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Aderência Bacteriana , Proteínas Sanguíneas/metabolismo , Materiais Revestidos Biocompatíveis , Etilenoglicol/metabolismo , Staphylococcus aureus/fisiologia , Propriedades de Superfície , Animais , Bovinos , Humanos , Imunoglobulina G/metabolismo , Ligação Proteica , Proteína Estafilocócica ARESUMO
Molecular dynamics simulations are used to interrogate the dynamic nature of Staphylococcus aureus Type I signal peptidases, SpsA and SpsB, including the impact of the P29S mutation of SpsB. Fluctuations and plasticity- rigidity characteristics vary among the proteins, particularly in the extracellular domain. Intriguingly, the P29S mutation, which influences susceptibility to arylomycin antibiotics, affect the mechanically coupled motions in SpsB. The integrity of the active site is crucial for catalytic competency, and variations in sampled structural conformations among the proteins are consistent with diverse peptidase capabilities. We also explored the intricate interactions between the proteins and the model S. aureus membrane. It was observed that certain membrane-inserted residues in the loop around residue 50 (50s) and C-terminal loops, beyond the transmembrane domain, give rise to direct interactions with lipids in the bilayer membrane. Our findings are discussed in the context of functional knowledge about these signal peptidases, offering additional understanding of dynamic aspects relevant to some cellular processes with potential implications for drug targeting strategies.
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In this editorial, written by early-career scientists, we advocate for the invaluable role of society journals in our scientific community. By choosing to support these journals as authors, peer reviewers, and as editors, we can reinforce our academic growth and benefit from their re-investment back into the scientific ecosystem. Considering the numerous clear merits of this system for future generations of microbiologists and more broadly, society, we argue that early-career researchers should publish our high-quality research in society journals to shape the future of science and scientific publishing landscape.
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Ecossistema , Publicações Periódicas como Assunto , Humanos , Editoração , Redação , PesquisadoresRESUMO
Hepatocellular carcinoma (HCC) remains a formidable malignancy that significantly impacts human health, and the early diagnosis of HCC holds paramount importance. Therefore, it is imperative to develop an efficacious signature for the early diagnosis of HCC. In this study, we aimed to develop early HCC predictors (eHCC-pred) using machine learning-based methods and compare their performance with existing methods. The enhancements and advancements of eHCC-pred encompassed the following: (i) utilization of a substantial number of samples, including an increased representation of cirrhosis tissues without HCC (CwoHCC) samples for model training and augmented numbers of HCC and CwoHCC samples for model validation; (ii) incorporation of two feature selection methods, namely minimum redundancy maximum relevance and maximum relevance maximum distance, along with the inclusion of eight machine learning-based methods; (iii) improvement in the accuracy of early HCC identification, elevating it from 78.15 to 97% using identical independent datasets; and (iv) establishment of a user-friendly web server. The eHCC-pred is freely accessible at http://www.dulab.com.cn/eHCC-pred/ . Our approach, eHCC-pred, is anticipated to be robustly employed at the individual level for facilitating early HCC diagnosis in clinical practice, surpassing currently available state-of-the-art techniques.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Diagnóstico Precoce , Cirrose Hepática , Aprendizado de Máquina , PrednisonaRESUMO
The inaugural Junior Editorial Board (JEB) of mBio consisted of 64 early-career researchers active from 2022 to 2023. The goal of the JEB was to train early-career researchers in the art of peer review under the guidance of experienced editors. JEB members gained hands-on experience in peer review by participating in modules detailing the publishing process through the lenses of the journal, editor, and reviewer. Ultimately, JEB members applied this new knowledge by reviewing mBio manuscripts. Here, we summarize the background, the mission, and the achievements of the first mBio JEB. We also include possible trajectories for the future editions of this important program.
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Revisão por Pares , Editoração , Humanos , Pesquisadores , Revisão da Pesquisa por ParesRESUMO
In this study, we attempted to adopt the auxotrophic mevalonate synthase mutant (ΔmvaS mutant) of Staphylococcus aureus to study whether a nongrowing but viable cell population is tolerant to bactericidal antibiotics. The mevalonate-depleted nongrowing ΔmvaS mutant was found tolerant to antibiotics. Surprisingly, after prolonged cultivation, we obtained stable ΔmvaS variants that were able to grow without mevalonate, which suggested unknown mechanisms for compensating undecaprenyl pyrophosphate production without mevalonate in S. aureus.
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Adaptação Fisiológica , Proteínas de Bactérias/genética , Ligases/genética , Ácido Mevalônico/metabolismo , Staphylococcus aureus/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Ciprofloxacina/farmacologia , Contagem de Colônia Microbiana , Daptomicina/farmacologia , Deleção de Genes , Teste de Complementação Genética , Gentamicinas/farmacologia , Ligases/deficiência , Testes de Sensibilidade Microbiana , Fosfatos de Poli-Isoprenil/metabolismo , Rifampina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimentoRESUMO
Heterogeneity is a critical basis for understanding how the tumor microenvironment (TME) contributes to tumor progression. However, an understanding of the specific characteristics and functions of TME subtypes (subTMEs) in the progression of cancer is required for further investigations into single-cell resolutions. Here, we analyzed single-cell RNA sequencing data of 250 clinical samples with more than 200,000 cells analyzed in each cancer datum. Based on the construction of an intercellular infiltration model and unsupervised clustering analysis, four, three, three, and four subTMEs were revealed in breast, colorectal, esophageal, and pancreatic cancer, respectively. Among the subTMEs, the immune-suppressive subTME (subTME-IS) and matrix remodeling with malignant cells subTME (subTME-MRM) were highly enriched in tumors, whereas the immune cell infiltration subTME (subTME-ICI) and precancerous state of epithelial cells subTME (subTME-PSE) were less in tumors, compared with paracancerous tissues. We detected and compared genes encoding cytokines, chemokines, cytotoxic mediators, PD1, and PD-L1. The results showed that these genes were specifically overexpressed in different cell types, and, compared with normal tissues, they were upregulated in tumor-derived cells. In addition, compared with other subTMEs, the expression levels of PDCD1 and TGFB1 were higher in subTME-IS. The Cox proportional risk regression model was further constructed to identify possible prognostic markers in each subTME across four cancer types. Cell-cell interaction analysis revealed the distinguishing features in molecular pairs among different subTMEs. Notably, ligand-receptor gene pairs, including COL1A1-SDC1, COL6A2-SDC1, COL6A3-SDC1, and COL4A1-ITGA2 between stromal and tumor cells, associated with tumor invasion phenotypes, poor patient prognoses, and tumor advanced progression, were revealed in subTME-MRM. C5AR1-RPS19, LGALS9-HAVCR2, and SPP1-PTGER4 between macrophages and CD8+ T cells, associated with CD8+ T-cell dysfunction, immunosuppressive status, and tumor advanced progression, were revealed in subTME-IS. The spatial co-location information of cellular and molecular interactions was further verified by spatial transcriptome data from colorectal cancer clinical samples. Overall, our study revealed the heterogeneity within the TME, highlighting the potential pro-invasion and pro-immunosuppressive functions and cellular infiltration characteristics of specific subTMEs, and also identified the key cellular and molecular interactions that might be associated with the survival, invasion, immune escape, and classification of cancer patients across four cancer types.
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An immunosuppressive state is regulated by various factors in the tumor microenvironment (TME), including, but not limited to, metabolic plasticity of immunosuppressive cells and cytokines secreted by these cells. We used single-cell RNA-sequencing (scRNA-seq) data and applied single-cell flux estimation analysis to characterize the link between metabolism and cellular function within the hypoxic TME of colorectal (CRC) and lung cancer. In terms of metabolic heterogeneity, we found myeloid cells potentially inclined to accumulate glutamine but tumor cells inclined to accumulate glutamate. In particular, we uncovered a tumor-associated macrophage (TAM) subpopulation, APOE+CTSZ+TAM, that was present in high proportions in tumor samples and exhibited immunosuppressive characteristics through upregulating the expression of anti-inflammatory genes. The proportion of APOE+CTSZ+TAM and regulatory T cells (Treg) were positively correlated across CRC scRNA-seq samples. APOE+CTSZ+TAM potentially interacted with Treg via CXCL16-CCR6 signals, as seen by ligand-receptor interactions analysis. Notably, glutamate-to-glutamine metabolic flux score and glutamine synthetase (GLUL) expression were uniquely higher in APOE+CTSZ+TAM, compared with other cell types within the TME. GLUL expression in macrophages was positively correlated with anti-inflammatory score and was higher in high-grade and invasive tumor samples. Moreover, spatial transcriptome and multiplex immunofluorescence staining of samples showed that APOE+CTSZ+TAM and Treg potentially colocalized in the tissue sections from CRC clinical samples. These results highlight the specific role and metabolic characteristic of the APOE+CTSZ+TAM subpopulation and provide a new perspective for macrophage subcluster-targeted therapeutic interventions or metabolic checkpoint-based cancer therapies.
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Glutamato-Amônia Ligase , Neoplasias Pulmonares , Macrófagos Associados a Tumor , Humanos , Apolipoproteínas E/genética , Expressão Gênica , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Glutamina , Fenótipo , Análise de Célula Única , Análise Espacial , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/metabolismoRESUMO
The objectives of this study were to incorporate dimethylaminohexadecyl methacrylate (DMAHDM) into resin-modified glass ionomer cement (RMGI) to develop a novel orthodontic cement which endowed RMGI with strong antibacterial ability and investigated its modulation biofilm equilibrium from cariogenic state to non-cariogenic state for the first time. Cariogenic Streptococcus mutans (S. mutans), and non-cariogenic Streptococcus sanguinis (S. sanguinis) and Streptococcus gordonii (S. gordonii) were selected to form a tri-species biofilm model. RMGI incorporated with different mass fraction of DMAHDM was examined: biofilm colony-forming units, metabolic activity, live/dead staining, lactic acid and exopolysaccharides productions. TaqMan real-time polymerase chain reaction was used to determine changes of biofilm species compositions. The results showed RMGI containing 3% DMAHDM achieved strong antibacterial ability and suppressed the cariogenic species in biofilm, modulating biofilm equilibrium from cariogenic state to non-cariogenic state tendency. The novel bioactive cement containing DMAHDM is promising in fixed orthodontic treatments and protecting tooth enamel.