Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS.

Self-nonself discrimination is vital for the immune system to mount responses against pathogens while maintaining tolerance toward the host and innocuous commensals during homeostasis. Here, we investigated how indiscriminate DNA sensors, such as cyclic GMP-AMP synthase (cGAS), make this self-nonself distinction. Screening of a small-molecule library revealed that spermine, a well-known DNA condenser associated with viral DNA, markedly elevates cGAS activation. Mechanistically, spermine condenses DNA to enhance and stabilize cGAS-DNA binding, optimizing cGAS and downstream antiviral signaling. Spermine promotes condensation of viral, but not host nucleosome, DNA. Deletion of viral DNA-associated spermine, by propagating virus in spermine-deficient cells, reduced cGAS activation. Spermine depletion subsequently attenuated cGAS-mediated antiviral and anticancer immunity. Collectively, our results reveal a pathogenic DNA-associated molecular pattern that facilitates nonself recognition, linking metabolism and pathogen recognition.

Organization of an Artificial Multicellular System with a Tunable DNA Patch on a Membrane Surface.

Coordinating multiple artificial cellular compartments into a well-organized artificial multicellular system (AMS) is of great interest in bottom-up synthetic biology. However, developing a facile strategy for fabricating an AMS with a controlled arrangement remains a challenge. Herein, utilizing in situ DNA hybridization chain reaction on the membrane surface, we developed a DNA patch-based strategy to direct the interconnection of vesicles. By tuning the DNA patch that generates heterotrophic adhesion for the attachment of vesicles, we could produce an AMS with higher-order structures straightforwardly and effectively. Furthermore, a hybrid AMS comprising live cells and vesicles was fabricated, and we found the hybrid AMS with higher-order structures arouses efficient molecular transportation from vesicles to living cells. In brief, our work provides a versatile strategy for modulating the self-assembly of AMSs, which could expand our capability to engineer synthetic biological systems and benefit synthetic cell research in programmable manipulation of intercellular communications.

Metabolic subtypes and immune landscapes in esophageal squamous cell carcinoma: prognostic implications and potential for personalized therapies.

BACKGROUND: This study aimed to identify metabolic subtypes in ESCA, explore their relationship with immune landscapes, and establish a metabolic index for accurate prognosis assessment. METHODS: Clinical, SNP, and RNA-seq data were collected from 80 ESCA patients from the TCGA database and RNA-seq data from the GSE19417 dataset. Metabolic genes associated with overall survival (OS) and progression-free survival (PFS) were selected, and k-means clustering was performed. Immune-related pathways, immune infiltration, and response to immunotherapy were predicted using bioinformatic algorithms. Weighted gene co-expression network analysis (WGCNA) was conducted to identify metabolic genes associated with co-expression modules. Lastly, cell culture and functional analysis were performed using patient tissue samples and ESCA cell lines to verify the identified genes and their roles. RESULTS: Molecular subtypes were identified based on the expression profiles of metabolic genes, and univariate survival analysis revealed 163 metabolic genes associated with ESCA prognosis. Consensus clustering analysis classified ESCA samples into three distinct subtypes, with MC1 showing the poorest prognosis and MC3 having the best prognosis. The subtypes also exhibited significant differences in immune cell infiltration, with MC3 showing the highest scores. Additionally, the MC3 subtype demonstrated the poorest response to immunotherapy, while the MC1 subtype was the most sensitive. WGCNA analysis identified gene modules associated with the metabolic index, with SLC5A1, NT5DC4, and MTHFD2 emerging as prognostic markers. Gene and protein expression analysis validated the upregulation of MTHFD2 in ESCA. MTHFD2 promotes the progression of ESCA and may be a potential therapeutic target for ESCA. CONCLUSION: The established metabolic index and identified metabolic genes offer potential for prognostic assessment and personalized therapeutic interventions for ESCA, underscoring the importance of targeting metabolism-immune interactions in ESCA. MTHFD2 promotes the progression of ESCA and may be a potential therapeutic target for ESCA.

The mediating effect of family resilience between coping styles and caregiver burden in maintenance hemodialysis patients: a cross-sectional study.

BACKGROUND: Primary caregivers of hemodialysis patients suffer from varying degrees of stress from their patients. Caring for hemodialysis patients can expose caregivers to many problems, leading to an increased burden of care and even impacting the quality of care. The purpose of our study was to examine whether family resilience could be a mediating variable moderating the relationship between patient coping styles and caregiver burden. METHODS: The study was a cross-sectional and descriptive-analytical study that interviewed 173 pairs of hemodialysis patients and their caregivers at a blood purification center in a public hospital in China. The Brief Coping Styles Scale (Chinese version) was used to assess individuals' coping styles for disease and treatment. From the caregiver's perspective, the Family Resilience Assessment Scale (Chinese version) was used to understand the resilience of families, and the Zarit Caregiver Burden Scale was used to capture the caregiver's subjective experience of burden. Statistical analyses were conducted using SPSS version 23 and Amos version 26 to analyze the relationships between variables to examine for correlation and construct mediated effects models. RESULTS: Coping styles showed a significant positive correlation with family resilience (r = 0.347, P < 0.01) and a negative correlation with caregiver burden (r = -0.379, P < 0.01). A significant negative correlation was found between family resilience and caregiver burden (r = -0.503, P < 0.01). In the mediation model, patient coping styles directly impacted caregiver burden significantly (95% CI [-0.372, -0.058]), and coping styles indirectly impacted caregiver burden by family resilience in a significant way (95% CI [-0.275, -0.098]). CONCLUSIONS: Patient coping styles directly affect caregiver burden. Family resilience is a mediating variable between patients' coping styles and the burden on caregivers.

circ_0000337 Promotes the Progression of Cervical Cancer by miR-155-5p/RAB3B Axis.

Current study aims to investigate the biological function of circular RNA (circRNA, circ_0000337) in cervical cancer (CC). Bioinformatic analyses were used to predict targets for circ_0000337 and miR-155-5p, and analyze the gene expression differences between cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues and normal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were applied to assess mRNA and protein expressions of circ_0000337, microRNA-155-5p (miR-155-5p) and member RAS oncogene family (RAB3B), respectively. Following the establishment of gain/loss-of-function models, CCK-8 was performed to evaluate cell proliferation. Bioinformatics analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) were used to identify the interaction in circ_0000337, miR-155-5p, and RAB3B. Circ_0000337 and RAB3B were upregulated, while miR-155-5p was downregulated in CC tissues and cell lines. circ_0000337 overexpression promoted cell proliferation, circ_0000337 knock down inhibited cell proliferation by sponging miR-155-5p. RAB3B was a target of miR-155-5p which was positively regulated by circ_0000337. In the collected CC tissues, there was a negative correlation between miR-155-5p and circ_0000337 or RAB3B, and a positive correlation between circ_0000337 and RAB3B. miR-155-5p was positively, while RAB3B was negatively correlated with OS in patients with CC, and they were negatively correlated. In conclusion, circ_0000337 upregulates RAB3B by sponging miR-155-5p to promote CC cell proliferation.

Recent Advances in DNA-Based Cell Surface Engineering for Biological Applications.

Due to its excellent programmability and biocompatibility, DNA molecule has unique advantages in cell surface engineering. Recent progresses provide a reliable and feasible way to engineer cell surfaces with diverse DNA molecules and DNA nanostructures. The abundant form of DNA nanostructures has greatly expanded the toolbox of DNA-based cell surface engineering and gave rise to a variety of novel and fascinating applications. In this review, we summarize recent advances in DNA-based cell surface engineering and its biological applications. We first introduce some widely used methods of immobilizing DNA molecules on cell surfaces and their application features. Then we discuss the approaches of employing DNA nanostructures and dynamic DNA nanotechnology as elements for creating functional cell surfaces. Finally, we review the extensive biological applications of DNA-based cell surface engineering and discuss the challenges and prospects of DNA-based cell surface engineering.

NADP modulates RNA m6A methylation and adipogenesis via enhancing FTO activity.

Metabolism is often regulated by the transcription and translation of RNA. In turn, it is likely that some metabolites regulate enzymes controlling reversible RNA modification, such as N6-methyladenosine (m6A), to modulate RNA. This hypothesis is at least partially supported by the findings that multiple metabolic diseases are highly associated with fat mass and obesity-associated protein (FTO), an m6A demethylase. However, knowledge about whether and which metabolites directly regulate m6A remains elusive. Here, we show that NADP directly binds FTO, independently increases FTO activity, and promotes RNA m6A demethylation and adipogenesis. We screened a set of metabolites using a fluorescence quenching assay and NADP was identified to remarkably bind FTO. In vitro demethylation assays indicated that NADP enhances FTO activity. Furthermore, NADP regulated mRNA m6A via FTO in vivo, and deletion of FTO blocked NADP-enhanced adipogenesis in 3T3-L1 preadipocytes. These results build a direct link between metabolism and RNA m6A demethylation.

Top-Down Production of Sustainable and Scalable Hemicellulose Nanocrystals.

Polysaccharide nanocrystals have led to the development of multifunctional and sustainable materials, but most are glucose-based carbohydrates derived from valuable natural sources. Here, we present a top-down strategy that enables one, for the first time, to isolate xylose-based hemicellulose nanocrystals from available industrial biowastes. By leveraging the selective oxidation of alkaline periodate, as high as 34 wt % solid yield is accessible. The hemicellulose nanocrystals exhibit platelet-like shapes (10-20 nm thickness, 30-80 nm wide), crystalline features, and superior dispersibility in water. We also showcase their successful interface applications for one-dimensional (1D) carbon nanotube (CNT) nanoinks and two-dimensional (2D) transition-metal dichalcogenide (TMD) nanozymes, which are comparable to the traditional cellulose nanocrystals. The scalable, low-cost, and sustainable hemicellulose nanocrystals can be envisioned to provide an alternative for glucose-based polysaccharide nanocrystals, as well as hold promise for the high-value utilization of biowastes.

Manipulation of Multiple Cell-Cell Interactions by Tunable DNA Scaffold Networks.

Manipulation of cell-cell interactions via cell surface engineering has potential biomedical applications in tissue engineering and cell therapy. However, manipulation of the comprehensive and multiple intercellular interactions remains a challenge and missing elements. Herein, utilizing a DNA triangular prism (TP) and a branched polymer (BP) as functional modules, we fabricate tunable DNA scaffold networks on the cell surface. The responsiveness of cell-cell recognition, aggregation and dissociation could be modulated by aptamer-functionalized DNA scaffold networks with high accuracy and specificity. By regulating the DNA scaffold networks coated on the cell surface, controlled intercellular molecular transportation is achieved. Our tunable network provides a simple and extendible strategy which addresses a current need in cell surface engineering to precisely manipulate cell-cell interactions and shows promise as a general tool for controllable cell behavior.

A Cascade Signaling Network between Artificial Cells Switching Activity of Synthetic Transmembrane Channels.

Cell-cell communication plays a vital role in biological activities; in particular, membrane-protein interactions are profoundly significant. In order to explore the underlying mechanism of intercellular signaling pathways, a full range of artificial systems have been explored. However, many of them are complicated and uncontrollable. Herein we designed an artificial signal transduction system able to control the influx of environmental ions by triggering the activation of synthetic transmembrane channels immobilized on giant membrane vesicles (GMVs). A membrane protein-like stimulator from one GMV community (GMVB) stimulates a receptor on another GMV community (GMVA) to release ssDNA messengers, resulting in the activation of synthetic transmembrane channels to enable the influx of ions. This event, in turn, triggers signal responses encapsulated in the GMVA protocell model. By mimicking natural signal transduction pathways, this novel prototype provides a workable tool for investigating cell-cell communication and expands biological signaling systems in general as well as explores useful platforms for addressing scientific problems which involve materials science, chemistry, and medicine.

G-Quadruplex-Induced Liquid-Liquid Phase Separation in Biomimetic Protocells.

Biomolecular condensates comprised of specific proteins and nucleic acids are now recognized as one of the key organizing mechanisms in eukaryotic cells. However, the specific roles played by the nucleic acid secondary structure and sequence in biomolecular phase separation are still not clear. Here, utilizing giant membrane vesicles (GMVs) as a protocell model, we found that single-stranded DNA (ssDNA) with a parallel G-quadruplex structure could functionally cooperate with a G-quadruplex-binding protein to form speckle-like puncta inside the GMVs. The clustering behavior is dependent on the structural diversity of G-quadruplexes, and the reversible clustering behavior implicated a new pathway in dynamically regulating the formation of biomolecular condensates. This finding represents a potential link between G-quadruplex-binding proteins and the resulting G-quadruplex-mediated biomolecular phase separation, which would gain insight into a wide range of biological processes associated with nucleic acid-modulated phase separation inside living cells.

Amplified Fluorescence by Hollow-Porous Plasmonic Assembly: A New Observation and Its Application in Multiwavelength Simultaneous Detection.

Surface plasmon coupled emission (SPCE) is a new analytical technique that provides increased and directional radiation based on the near-field interaction between fluorophores and surface plasmons but suffers from the limitation of insufficient sensitivity. The assembly of hollow-porous plasmonic nanoparticles could be the qualified candidate. After the introduction of gold nanocages (AuNCs), fluorescence signal enhancement was realized by factors over 150 and 600 compared with the normal SPCE and free space emission, respectively, with a fluorophore layer thickness of approximately 10 nm; hence, the unique enhancement of SPCE by the AuNCs effectively overcomes the signal quenching induced by resonance energy transfer (in normal SPCE). This enhancement was proven to be triggered by the superior wavelength match, the enhanced electromagnetic field, and new radiation channel and process induced by the AuNC assembly, which provides an opportunity to increase the detection sensitivity and establish an optimal plasmonic enhancement system. The amplified SPCE system was employed for multiwavelength simultaneous enhancement detection through the assembly of mixed hollow nanoparticles (AuNCs and gold nanoshells), which could broaden the application of SPCE in simultaneous sensing and imaging for multianalytes.

A spiropyran functionalized fluorescent probe for mitochondria targeting and imaging of endogenous hydrogen sulfide in living cells.

A turn-on spiropyran functionalized fluorescein derivative (FMC) is developed for targeting HS- in mitochondria. FMC exhibits very weak fluorescence at 525 nm under the excitation of 470 nm in aqueous solution due to its colorless spiropyran form; upon addition of HS-, a strong fluorescence enhancement by 6.4-fold is observed with spirocycle-opened merocyanine form and rapid trapping kinetics for HS-. FMC has good biocompatibility and high selectivity towards HS- with a detection limit of 88.2 nM and is very sensitive among the reported H2S fluorescent probes. Moreover, the significant colocalization of FMC with Mito Tracker® Deep Red FM in human laryngeal epidermoid carcinoma (HEp-2) cells and the Pearson correlation coefficient of 0.87 together demonstrate that FMC can target and image the endogenous H2S in the mitochondria of living cells.

Maternal risk factors and pregnancy complications associated with low birth weight neonates in preterm birth.

AIM: To explore the association between common pregnancy complications and low birth weight (LBW) neonates in preterm birth. METHODS: The study included 1764 pregnant women who experienced a single birth prematurely at a city hospital in Guangzhou, China between January 1, 2017 and December 31, 2019. A total of 874 normal birth weight neonates and 890 LBW neonates were included. Multivariate logistic regression analysis was conducted to identify and measure risk factors; two-tailed test was applied, with a p ≤ 0.05 considered statistically significant. RESULTS: Hypertension was the primary risk factor of LBW in preterm neonates, odds ratio (OR) = 2.912 (p < 0.001; 95% confidence interval [CI], 2.044-4.149), followed by hypothyroidism, OR = 1.807 (p = 0.046; 95% CI, 1.012-3.226), placental abruption, OR = 1.759 (p = 0.049; 95% CI, 1.002-3.087), reproductive tract infection, OR = 1.746 (p < 0.001; 95% CI, 1.325-2.301), abnormal amniotic fluid volume, OR = 1.737 (p = 0.003; 95% CI, 1.202-2.501), and fetal distress OR = 1.690 (p = 0.012; 95% CI, 1.120-2.551). CONCLUSION: Preventing risk factors, such as hypertension, hypothyroidism, and reproductive tract infections, during pregnancy may reduce the incidence of LBW neonates.

Enhanced electrochemiluminescence of Ru(bpy)3 2+ -doped silica nanoparticles by chitosan/Nafion shell@carbon nanotube core-modified electrode.

Although Ru(bpy)3 2+ -doped silica nanoparticles have been widely explored as the labelling tags for electrochemiluminescence (ECL) sensing different targets, the poor electrical conductive properties of the silica nano-matrix greatly limit their ECL sensitivity. Therefore, a novel scheme to overcome this drawback on Ru(bpy)3 2+ -doped silica nanoparticles ECL is desirable. Here, a new scheme for this purpose was developed based on electrochemically depositing a nanoscale chitosan hydrogel layer on the carbon nanotube (CNT) surface to form chitosan hydrogel shell@CNT core nanocomposites. In this case, the nanoscale chitosan hydrogel layer only formed on the CNT surface due to the superior electrocatalytic effect of CNT on H+ reduction compared with the basic glass carbon electrode. Due to both the superhydrophilic properties and polyelectrolyte features of nanoscale chitosan hydrogel on the CNT surface, chemical affinity as well as the electric conductivity between Ru(bpy)3 2+ -doped silica nanoparticles and CNT were obviously enhanced, and then the ECL effectivity of Ru(bpy)3 2+ inside silica nanoparticles was improved. Furthermore, based on the discriminative interaction of these Ru(bpy)3 2+ -doped silica nanoparticles towards both the ssDNA probes and the ssDNA probe/miRNA complex, as well as the specific adsorption effect of these nanoparticles on the nanoscale chitosan shell@Nafion/CNT core-modified glass carbon electrode, a highly sensitive ECL method for miRNA determination was developed and successfully used to detect miRNA in human serum samples.

Subunits of ARID1 serve as novel biomarkers for the sensitivity to immune checkpoint inhibitors and prognosis of advanced non-small cell lung cancer.

INTRODUCTION: Patients with advanced non-small cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Biomarkers such as programmed death-ligand 1 (PD-L1), the tumor mutational burden (TMB) and the mismatch repair (MMR) status are used to predict the prognosis of ICIs therapy. Nevertheless, novel biomarkers need to be further investigated, and a systematic prognostic model is needed for the evaluation of the survival risks of ICIs treatment. METHODS: A cohort of 240 patients who received ICIs from the cBioPortal for Cancer Genomics was evaluated in this research. Clinical information and targeted sequencing data were acquired for analyses. The Kaplan-Meier plot method was used to perform survival analyses, and selected variables were then confirmed by a novel nomogram constructed by the "rms" package of R software. RESULTS: Seven percent of the NSCLC patients harbored ARID1A mutations, while 4% of the NSCLC patients harbored ARID1B mutations. Mutations in ARID1A and ARID1B were confirmed to be associated with sensitivity to ICIs. Patients harboring these mutations were found to have a better response to treatment (ARID1A: P = 0.045; ARID1B: P = 0.034) and prolonged progression-free survival (ARID1B: P = 0.032). Here, a novel nomogram was constructed to predict the prognosis of ICIs treatment. Elevation of the TMB, enhanced expression of PD-L1 and activation of the antigen presentation process and cellular immunity were found to be correlated with ARID1A and ARID1B mutations. CONCLUSION: ARID1A and ARID1B could serve as novel biomarkers for the prognosis and sensitivity to ICIs of advanced NSCLC.

The role of CD28 in the prognosis of young lung adenocarcinoma patients.

BACKGROUND: The prognosis of lung cancer was found to be associated with a series of biomarkers related to the tumor immune microenvironment (TIME), which can modulate the biological behaviors and consequent outcomes of lung cancer. Therefore, establishing a prognostic model based on the TIME for lung cancer patients, especially young patients with lung adenocarcinoma (LUAD), is urgently needed. METHODS: In all, 809 lung cancer patients from the TCGA database and 71 young patients with LUAD in our center were involved in this study. Univariate and multivariate analysis based on clinical characteristics and TIME-related expression patterns (as evaluated by IHC) were performed to estimate prognosis and were verified by prognostic nomograms. RESULTS: Both LUAD and lung cancer patients with high CD28 expression had shorter disease-free survival (DFS) (P = 0.0011; P = 0.0001) but longer overall survival (OS) (P = 0.0001; P = 0.0282). TIME-related molecules combined with clinical information and genomic signatures could predict the prognosis of young patients with LUAD with robust efficiency and could be verified by the established nomogram based on the Cox regression model. In addition, CD28 expression was correlated with an abundance of lymphocytes and could modulate the TIME. Higher CD28 levels were observed in primary tumors than in metastatic tissues. CONCLUSION: TIME-related molecules were identified as compelling biomarkers for predicting the prognosis of lung cancer, especially in a cohort of young patients. Furthermore, CD28, which is associated with poor DFS but long OS, might participate in the modulation of the TIME and has a different role in the prognosis of young patients with LUAD.

Comparison of city-level carbon footprint evaluation by applying single- and multi-regional input-output tables.

City-level carbon footprint has been recognized as a useful measure of anthropogenic impact on climate change associated with citizens' activities within the administrative boundary. Although the promotion of consumer responsibility suggests rethinking urban indirect emissions, the detailed methodology is far from satisfactory for realistic applications. Due to the lack of multi-regional input-output tables for most cities, there is a wide application of single regional input-output tables. However, there still lacks further discussion on if there will be an obvious evaluation bias by applying city-level single-regional tables rather than multi-regional ones. To visualize the table coverage on its application consequence, both single- and multi-regional input-output tables were employed to compare disparities in the carbon footprint accounting in the case of Tokyo, Japan. Our analysis shows that the gap of emissions driven by Tokyo's final demand between single- and multi-regional input-output tables was considerably large. Furthermore, the results of multi-regional table were found to be 8.11 MtC higher for coal-generated emissions, 7.83 MtC for crude oil-generated emissions and 2.90 MtC for natural gas-generated emissions than those of the single-regional table. The largest deviation in emissions accounting was observed in the power, gas and heating supply sector, the construction sector and the private service sector. The gap between these two input-output tables was notable for all three types of fossil fuels (coal, crude oil and natural gas). These indicated that coal-generated emissions have been largely ignored by single-regional input-output table. The study highlighted the difference of carbon footprint accounting between these two types of input-output tables. Our findings are intended to assist policymakers and scholars in pinpointing and reallocating sectors that are likely to yield severely biased evaluation of emissions embodied in trade when a multi-regional table is not available.

[Clinicopathological Features of Follicular Dendritic Cell Sarcoma].

Objective To explore the clinicopathological and immunohistochemical characteristics of follicular dendritic cell sarcoma(FDCS)and the expressions of IgG and IgG4. Methods We retrospectively analyzed the clinicopathological and immunohistochemical data of 9 pathologically confirmed FDCS cases in Peking Union Medical College Hospital from January 2005 to December 2018.Immunohistochemical staining of IgG and IgG4 were performed,and Epstein-Barr virus(EBV)-encoded RNA(EBER)in situ hybridization were carried out. Results Nine cases of FDCS included 4 men and 5 women aged 16-53 years [mean(38.2±9.7)years].The clinical manifestations included masses,lymph node enlargement,rash,and fever.The tumors were located in lymph node,retroperitoneal region,adrenal gland,neck,axillary region,and liver,respectively.Ultrasound showed clear boundary cystic or solid mass with maximum diameters of 1.5-15.0 cm.Microscopically,the spindle tumor cells were arranged in solid and storiform patterns with abundant and slightly stained cytoplasm,vacuolated nuclei,and small nucleoli.The mitosis was 1-3/10 high power fields,and necrosis was found in 5 cases.Immunohistochemically,the tumor cells were positive for CD21(6/9),CD35(6/9),and CD23(7/9). Conclusions FDCS is a rare malignant tumor,which is easy to be missed.The combination of CD21,CD35,and CD23 is helpful for diagnosis.Hyaline-vascular type Castleman's disease may be the precursor of FDCS,and there may be only a small number of IgG4-positive plasma cells in FDCS.Surgical resection remains the main treatment for FDCS.