Bifunctional Mo2N Nanoparticles with Nanozyme and SERS Activity: A Versatile Platform for Sensitive Detection of Biomarkers in Serum Samples.

The combined application of nanozymes and surface-enhanced Raman scattering (SERS) provides a promising approach to obtain label-free detection. However, developing nanomaterials with both highly efficient enzyme-like activity and excellent SERS sensitivity remains a huge challenge. Herein, we proposed one-step synthesis of Mo2N nanoparticles (NPs) as a "two-in-one" substrate, which exhibits both excellent peroxidase (POD)-like activity and high SERS activity. Its mimetic POD activity can catalyze the 3,3',5,5'-tetramethylbenzidine (TMB) molecule to SERS-active oxidized TMB (ox-TMB) with high efficiency. Furthermore, combining experimental profiling with theory, the mechanism of POD-like activity and SERS enhancement of Mo2N NPs was explored in depth. Benefiting from the outstanding properties of Mo2N NPs, a versatile platform for indirect SERS detection of biomarkers was developed based on the Mo2N NPs-catalyzed product ox-TMB, which acts as the SERS signal readout. The feasibility of this platform was validated using glutathione (GSH) and target antigens alpha-fetoprotein antigen (AFP) and carcinoembryonic antigen (CEA) as representatives of small molecules with a hydroxyl radical (·OH) scavenging effect and proteins with a low Raman scattering cross-section, respectively. The limits of detection of GSH, AFP, and CEA were as low as 0.1 µmol/L, 89.1, and 74.6 pg/mL, respectively. Significantly, it also showed application in human serum samples with recoveries ranging from 96.0 to 101%. The acquired values based on this platform were compared with the standard electrochemiluminescence method, and the relative error was less than ±7.3. This work not only provides a strategy for developing highly active bifunctional nanomaterials but also manifests their widespread application for multiple biomarkers analysis.

Effect modification of time spent outdoors on the association between early childhood overweight and myopia: a one-year follow-up study.

BACKGROUND: This study examined the moderating role of outdoor time on the relationship between overweight and myopia. METHODS: The data for this study was obtained from a prospective study in Shanghai, where non-myopic children wore wristwear and were followed up for 1 year. Eye examinations were performed at each visit. The modification effect was assessed on the additive scale using multivariable logistic regression, and relative excess risk due to interaction was used to calculate the modification effect. RESULTS: A total of 4683 non-myopic children were included with 32.20% being overweight at baseline. Following a 1-year period, 17.42% of children had myopia. When compared to those who spent <90 minutes outdoors, children who spent >120 had a relative risk of myopia onset that was reduced to 0.61. As time spent outdoors decreased, more risks of myopia onset were identified among overweight children than among normal children, the modification effect on the additive scale was -0.007, with ~70% of this effect attributed to the modifying influence of outdoor time. CONCLUSIONS: Increasing outdoor time can reduce myopia more among overweight children than normal. Future interventions should focus on outdoor activities among overweight children to reduce myopia risks.

The role of information industry convergence in energy transition.

To cope with global climate risks, promoting energy transformation has become a global consensus. China issued a reform policy in 2010 to promote the convergence of the three major information industries, namely broadcasting and television networks, telecommunications networks and the Internet (TPR policy). However, is the convergence of information industries able to promote energy transition? This study constructs a quasi-natural experimental framework using China's TPR policy as a representative case of industrial convergence. Using city-level panel data between 2003 and 2016 in China and a multi-period difference-in-differences model, this study examines the impact of TPR policy on energy transition. The results show that TPR policy positively contributes to energy transition at a 1% significance level. Extensive robustness tests support this finding. This positive effect is particularly evident in regions with less developed communications infrastructure and stricter environmental regulations. Mechanism analysis suggests that TPR policy promotes energy transition by improving the level of information networks, promoting technological innovation, and optimizing industrial structure. The findings of this paper emphasize the importance of information industry convergence in facilitating energy transformation.

Fatal Case of Heartland Virus Disease Acquired in the Mid-Atlantic Region, United States.

Heartland virus (HRTV) disease is an emerging tickborne illness in the midwestern and southern United States. We describe a reported fatal case of HRTV infection in the Maryland and Virginia region, states not widely recognized to have human HRTV disease cases. The range of HRTV could be expanding in the United States.

Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response.

Hantavirus nucleocapsid protein (NP) inhibits protein kinase R (PKR) dimerization by an unknown mechanism to counteract its antiviral responses during virus infection. Here we demonstrate that NP exploits an endogenous PKR inhibitor P58IPK to inhibit PKR. The activity of P58IPK is normally restricted in cells by the formation of an inactive complex with its negative regulator Hsp40. On the other hand, PKR remains associated with the 40S ribosomal subunit, a unique strategic location that facilitates its free access to the downstream target eIF2α. Although both NP and Hsp40 bind to P58IPK, the binding affinity of NP is much stronger compared to Hsp40. P58IPK harbors an NP binding site, spanning to N-terminal TPR subdomains I and II. The Hsp40 binding site on P58IPK was mapped to the TPR subdomain II. The high affinity binding of NP to P58IPK and the overlap between NP and Hsp40 binding sites releases the P58IPK from its negative regulator by competitive inhibition. The NP-P58IPK complex is selectively recruited to the 40S ribosomal subunit by direct interaction between NP and the ribosomal protein S19 (RPS19), a structural component of the 40S ribosomal subunit. NP has distinct binding sites for P58IPK and RPS19, enabling it to serve as bridge between P58IPK and the 40S ribosomal subunit. NP mutants deficient in binding to either P58IPK or RPS19 fail to inhibit PKR, demonstrating that selective engagement of P58IPK to the 40S ribosomal subunit is required for PKR inhibition. Cells deficient in P58IPK mount a rapid PKR antiviral response and establish an antiviral state, observed by global translational shutdown and rapid decline in viral load. These studies reveal a novel viral strategy in which NP releases P58IPK from its negative regulator and selectively engages it on the 40S ribosomal subunit to promptly combat the PKR antiviral responses.

The Properties of Linezolid, Rifampicin, and Vancomycin, as Well as the Mechanism of Action of Pentamidine, Determine Their Synergy against Gram-Negative Bacteria.

Combining pentamidine with Gram-positive-targeting antibiotics has been proven to be a promising strategy for treating infections from Gram-negative bacteria (GNB). However, which antibiotics pentamidine can and cannot synergize with and the reasons for the differences are unclear. This study aimed to identify the possible mechanisms for the differences in the synergy of pentamidine with rifampicin, linezolid, tetracycline, erythromycin, and vancomycin against GNB. Checkerboard assays were used to detect the synergy of pentamidine and the different antibiotics. To determine the mechanism of pentamidine, fluorescent labeling assays were used to measure membrane permeability, membrane potential, efflux pump activity, and reactive oxygen species (ROS); the LPS neutralization assay was used to evaluate the target site; and quantitative PCR was used to measure changes in efflux pump gene expression. Our results revealed that pentamidine strongly synergized with rifampicin, linezolid, and tetracycline and moderately synergized with erythromycin, but did not synergize with vancomycin against E. coli, K. pneumoniae, E. cloacae, and A. baumannii. Pentamidine increased the outer membrane permeability but did not demolish the outer and inner membranes, which exclusively permits the passage of hydrophobic, small-molecule antibiotics while hindering the entry of hydrophilic, large-molecule vancomycin. It dissipated the membrane proton motive force and inactivated the efflux pump, allowing the intracellular accumulation of antimicrobials that function as substrates of the efflux pump, such as linezolid. These processes resulted in metabolic perturbation and ROS production which ultimately was able to destroy the bacteria. These mechanisms of action of pentamidine on GNB indicate that it is prone to potentiating hydrophobic, small-molecule antibiotics, such as rifampicin, linezolid, and tetracycline, but not hydrophilic, large-molecule antibiotics like vancomycin against GNB. Collectively, our results highlight the importance of the physicochemical properties of antibiotics and the specific mechanisms of action of pentamidine for the synergy of pentamidine-antibiotic combinations. Pentamidine engages in various pathways in its interactions with GNB, but these mechanisms determine its specific synergistic effects with certain antibiotics against GNB. Pentamidine is a promising adjuvant, and we can optimize drug compatibility by considering its functional mechanisms.

Transcriptome Sequencing and Metabolome Analysis Reveals the Molecular Mechanism of Drought Stress in Millet.

As one of the oldest agricultural crops in China, millet (Panicum miliaceum) has powerful drought tolerance. In this study, transcriptome and metabolome analyses of 'Hequ Red millet' (HQ) and 'Yanshu No.10' (YS10) millet after 6 h of drought stress were performed. Transcriptome characteristics of drought stress in HQ and YS10 were characterized by Pacbio full-length transcriptome sequencing. The pathway analysis of the differentially expressed genes (DEGs) showed that the highly enriched categories were related to starch and sucrose metabolism, pyruvate metabolism, metabolic pathways, and the biosynthesis of secondary metabolites when the two millet varieties were subjected to drought stress. Under drought stress, 245 genes related to energy metabolism were found to show significant changes between the two strains. Further analysis showed that 219 genes related to plant hormone signal transduction also participated in the drought response. In addition, numerous genes involved in anthocyanin metabolism and photosynthesis were confirmed to be related to drought stress, and these genes showed significant differential expression and played an important role in anthocyanin metabolism and photosynthesis. Moreover, we identified 496 transcription factors related to drought stress, which came from 10 different transcription factor families, such as bHLH, C3H, MYB, and WRKY. Further analysis showed that many key genes related to energy metabolism, such as citrate synthase, isocitrate dehydrogenase, and ATP synthase, showed significant upregulation, and most of the structural genes involved in anthocyanin biosynthesis also showed significant upregulation in both strains. Most genes related to plant hormone signal transduction showed upregulated expression, while many JA and SA signaling pathway-related genes were downregulated. Metabolome analysis was performed on 'Hequ red millet' (HQ) and 'Yanshu 10' (YS10), a total of 2082 differential metabolites (DEMs) were identified. These findings indicate that energy metabolism, anthocyanins, photosynthesis, and plant hormones are closely related to the drought resistance of millet and adapt to adversity by precisely regulating the levels of various molecular pathways.

Magneto-refractive properties and measurement of an erbium-doped fiber.

The magneto-refractive properties of an erbium-doped fiber (EDF) are investigated by theoretically analyzing the change in mode characteristics with a magnetic field and experimentally measuring it based on a fiber-optic Mach-Zehnder interferometer (MZI). The numerical results indicate that the mode effective refractive index (RI) increases as the magnetic field increases, and the mode field intensity distribution tends to be more concentrated in the core region with an increasing magnetic field. The variation in the mode effective RI of the fundamental mode with the magnetic field is greater than that of the higher-order modes. A magneto-refractive measurement system based on a fiber-optic MZI is set up to analyze the magneto-refractive effect of the EDF. The changes in the mode effective RI measured with a direct-current (DC) magnetic field and with a 100 Hz alternating-current (AC) magnetic field are 4.838×10-6 and 4.245×10-6 RIU/mT, respectively. The experimental results are in reasonable agreement with the theoretical analysis. Furthermore, the error between the experimental and numerical results is discussed. The magneto-refractive properties of the EDF exhibit potential in all-fiber magnetic field or current sensing area.

Role of Sirtuin-1 in Neonatal Hypoxic-Ischemic Encephalopathy and Its Underlying Mechanism.

BACKGROUND Neonatal hypoxic-ischemic encephalopathy (HIE) is a dreaded disease and one of the leading causes of severe neurological dysfunction in neonates. The present study explored the functions of Sirtuin-1 (SIRT1) in neonatal HIE. MATERIAL AND METHODS A HIE neonatal rat model was generated to determine SIRT1 levels in brain tissues. Cell apoptosis and cell viability were analyzed by flow cytometry and MTT assay. qRT-PCR and Western blot analysis were used to assess gene mRNA and protein levels. Subsequently, the effect of SIRT1 on HIE was investigated in vitro by constructing an oxygen-glucose deprivation (OGD) cell model. RESULTS The effective construction of the HIE rat model was confirmed by the enhanced brain cell apoptosis and the increased expression of HIE-related molecular markers, including S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE). SIRT1 expression was downregulated in HIE rat brain tissues. These findings indicated that SIRT1 was downregulated in neuronal cells subjected to OGD. In addition, enhanced cell viability and reduced cell apoptosis were observed, suggesting that SIRT1 overexpression relieved OGD-induced neuronal cell injury. Transfection with SIRT1-siRNA further increased OGD-induced neuronal cell injury, evidenced by decreased cell viability and enhanced cell apoptosis. Finally, SIRT1 overexpression significantly downregulated p-p65 protein expression. CONCLUSIONS Our findings revealed that SIRT1 may be a novel and promising therapy target for HIE treatment.

Exosome-mediated targeted delivery of miR-210 for angiogenic therapy after cerebral ischemia in mice.

BACKGROUND: Accumulating evidence shows that microRNA-210 (miR-210) holds great promise to improve angiogenesis for brain tissue repair after cerebral ischemia. However, safe and efficient delivery of miR-210 via intravenous administration is still a challenge. In the past decade, exosomes have emerged as a novel endogenous delivery system. Here, c(RGDyK) peptide is conjugated to exosomes, and they are loaded with cholesterol-modified miR-210 (RGD-exo:miR-210). RESULTS: In a transient middle cerebral artery occlusion (MCAO) mouse model, the RGD-exo:miR-210 targets the lesion region of the ischemic brain after intravenous administration, resulting in an increase in miR-210 at the site. Furthermore, RGD-exo:miR-210 are administered once every other day for 14 days, and the expressions of integrin ß3, vascular endothelial growth factor (VEGF) and CD34 are significantly upregulated. The animal survival rate is also enhanced. CONCLUSIONS: These results suggest a strategy for the targeted delivery of miR-210 to ischemic brain and provide an angiogenic agent for the treatment of ischemic stroke.

Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis.

The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic ß cells by bile acids induces insulin secretion. Glucagon released from pancreatic α cells and glucagon-like peptide 1 (GLP-1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP-1 are derived from alternate splicing of a common precursor, proglucagon by PC2 and PC1, respectively. We investigated whether TGR5 activation in pancreatic α cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases ß cell mass and function in a paracrine manner. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in human and mouse islet α cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from α cells was via an Epac-mediated PKA-independent mechanism. Administration of the TGR5 agonist, INT-777, to db/db mice attenuated the increase in body weight and improved glucose tolerance and insulin sensitivity. INT-777 augmented PC1 expression in α cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic ß cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from α cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between α and ß cells by switching from glucagon to GLP-1 to restore ß cell mass and function under hyperglycemic conditions. Thus, INT-777-mediated TGR5 activation could be leveraged as a novel way to treat type 2 diabetes mellitus.

Soil bacterial diversity changes in different broomcorn millet intercropping systems.

Plants growing in soil and the diverse microorganisms with which they are in direct contact have adapted to exploit their close association for mutual benefit. Various intercropping systems have been used to control plant disease and improve productivity in fields. Although high-throughput sequencing approaches have provided new insights into the soil bacterial community, current knowledge of intercropping of broomcorn millet with different leguminous plants is limited. In this study, characterization of different bacterial communities of monoculture and intercropping systems was achieved by deep sequencing. A total of 4684 operational taxonomic units were classified to the species level with good sampling depth and sequencing coverage. The abundance of Actinobacteria, Bacteroidetes, Proteobacteria, Acidobacteria, and Gemmatimonadetes varied at different growth stages and was related to growth of the intercropped plant. According to diversity analyses, Glycomyces, Aeromicrobium, Adhaeribacter, and Streptomyces were the dominant genera. In addition, we predicted functional gene composition based on bacterial OTUs present. Functional results showed that membrane transport and nutrient metabolism was highly abundant in all samples, although abundance varied at different growth stages, which indicated these pathways might be affected by the dominant categories of bacterial community. The dynamic changes observed during intercropping of broomcorn millet with different leguminous plants suggest that soil bacterial community structure exhibits a crop species-specific pattern. Further, agronomic trait data from different broomcorn millet intercropping systems were consistent with functional results and suggest that agronomic traits may be influenced by soil bacterial communities.

Transcriptomic analysis reveals key early events of narciclasine signaling in Arabidopsis root apex.

KEY MESSAGE: Histochemical staining and RNA-seq data demonstrated that the ROS- and plant hormone-regulated stress responses are the key early events of narciclasine signaling in Arabidopsis root cells. Narciclasine, an amaryllidaceae alkaloid isolated from Narcissus tazetta bulbs, employs a broad range of functions on plant development and growth. However, its molecular interactions that modulate these roles in plants are not fully understood. To elucidate the global responses of Arabidopsis roots to short-term narciclasine exposure, we first measured the accumulation of H2O2 and O2- with histochemical staining, and then profiled the gene expression pattern in Arabidopsis root tips treated with 0.5 µM narciclasine across different exposure times by RNA-seq. Physiological measurements showed a significant increase in H2O2 began at 30-60 min of narciclasine treatment and O2- accumulated by 120 min. Compared with controls, 236 genes were upregulated and 54 genes were downregulated with 2 h of narciclasine treatment, while 968 genes were upregulated and 835 genes were downregulated with 12 h of treatment. The Gene Ontology analysis revealed that the differentially expressed genes were highly enriched during oxidative stress, including those involved in the "regulation of transcription", "response to oxidative stress", "plant-pathogen interaction", "ribonucleotide binding", "plant cell wall organization", and "ribosome biogenesis". Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment statistics suggested that carbohydrate metabolism, amino acid metabolism, amino sugar and nucleotide sugar metabolism, and biosynthesis of phenylpropanoid and secondary metabolites were significantly inhibited by 12 h of narciclasine exposure. Hence, our results demonstrate that hormones and H2O2 are important regulators of narciclasine signaling and help to uncover the factors involved in the molecular interplay between narciclasine and phytohormones in Arabidopsis root cells.

Urban public services and fertility intentions of internal migrants in China.

As China continues to implement its progressive fertility promotion policy, there has been a drastic decline in the fertility rate. Given that the migrant population constitutes more than a quarter of China's total population, enhancing the willingness of this demographic to have additional children through policy-guided urban public services is pivotal for optimizing China's population development strategy. This study analyzes the influence of urban public services on the reproductive intentions of the migrant population, utilizing data from 110,667 migrant families with one child, drawn from China's Migrant Population Dynamic Monitoring data in 2016 and 2018. The data analysis reveals several key findings: (1) Urban public services, overall, exhibit a notable positive effect on the willingness of the migrant population to have more children, albeit with limitations and a declining trend. (2) Among urban public services, primary basic education significantly impacts the willingness of the migrant population to expand their families. (3) Large cities have created a 'reverse screening' effect on the migrant population, leading to differential access to public services. This scenario caters effectively to the high human capital migrant individuals while reducing accessibility to livelihood public services for the low human capital migrant population. This paper critically evaluates China's progressively adjusted fertility policy from the perspective of the migrant population. It underscores the necessity of establishing a comprehensive fertility support policy system across China.

Simplified Methods for Modelling Dependent Parameters in Health Economic Evaluations: A Tutorial.

BACKGROUND: In health economic evaluations, model parameters are often dependent on other model parameters. Although methods exist to simulate multivariate normal (MVN) distribution data and estimate transition probabilities in Markov models while considering competing risks, they are technically challenging for health economic modellers to implement. This tutorial introduces easily implementable applications for handling dependent parameters in modelling. METHODS: Analytical proofs and proposed simplified methods for handling dependent parameters in typical health economic modelling scenarios are provided, and implementation of these methods are illustrated in seven examples along with the SAS and R code. RESULTS: Methods to quantify the covariance and correlation coefficients of correlated variables based on published summary statistics and generation of MVN distribution data are demonstrated using examples of physician visits data and cost component data. The use of univariate normal distribution data instead of MVN distribution data to capture population heterogeneity is illustrated based on the results from multiple regression models with linear predictors, and two examples are provided (linear fixed-effects model and Cox proportional hazards model). A conditional probability method is introduced to handle two or more state transitions in a single Markov model cycle and applied in examples of one- and two-way state transitions. CONCLUSIONS: This tutorial proposes an extension of routinely used methods along with several examples. These simplified methods may be easily applied by health economic modellers with varied statistical backgrounds.

Combining with domiphen bromide restores colistin efficacy against colistin-resistant Gram-negative bacteria in vitro and in vivo.

Today, colistin is considered a last-resort antibiotic for treating multidrug-resistant (MDR) Gram-negative bacteria (GNB). However, the increased and improper use of colistin has led to the emergence of colistin-resistant (Col-R) GNB. Thus, it is urgent to develop new drugs and therapies in response to the ongoing emergence of colistin resistance. In this study, we investigated the antibacterial and antibiofilm activities of the quaternary ammonium compound domiphen bromide (DB) in combination with colistin against clinical Col-R GNB both in vitro and in vivo. Checkerboard assay and time-kill analysis demonstrated significant synergistic antibacterial effects of the colistin/DB combination. The synergistic antibiofilm activity was confirmed through crystal violet staining and scanning electron microscopy (SEM). Furthermore, the colistin/DB combination exhibited increased survival rates in infected larvae and reduced bacterial loads in a mouse thigh infection model. The cytotoxicity measurement and hemolysis test showed that the combination did not adversely affect cell viability at synergistic concentrations. The alkaline phosphatase (ALP) leak test and propidium iodide (PI) staining analysis further revealed that the colistin/DB combination enhanced the therapeutic effect of colistin by altering bacterial membrane permeability. The ROS assays revealed that the combination induced the accumulation of bacterial ROS, leading to bacterial death. In conclusion, our study is the first to identify DB as a colistin potentiator, effectively restoring the sensitivity of bacteria to colistin. It provides a promising alternative approach for combating Col-R GNB infections.

Dilemmas and prospects of artificial intelligence technology in the data management of medical informatization in China: A new perspective on SPRAY-type AI applications.

Objectives: This study aims to address the critical challenges of data integrity, accuracy, consistency, and precision in the application of electronic medical record (EMR) data within the healthcare sector, particularly within the context of Chinese medical information data management. The research seeks to propose a solution in the form of a medical metadata governance framework that is efficient and suitable for clinical research and transformation. Methods: The article begins by outlining the background of medical information data management and reviews the advancements in artificial intelligence (AI) technology relevant to the field. It then introduces the "Service, Patient, Regression, base/Away, Yeast" (SPRAY)-type AI application as a case study to illustrate the potential of AI in EMR data management. Results: The research identifies the scarcity of scientific research on the transformation of EMR data in Chinese hospitals and proposes a medical metadata governance framework as a solution. This framework is designed to achieve scientific governance of clinical data by integrating metadata management and master data management, grounded in clinical practices, medical disciplines, and scientific exploration. Furthermore, it incorporates an information privacy security architecture to ensure data protection. Conclusion: The proposed medical metadata governance framework, supported by AI technology, offers a structured approach to managing and transforming EMR data into valuable scientific research outcomes. This framework provides guidance for the identification, cleaning, mining, and deep application of EMR data, thereby addressing the bottlenecks currently faced in the healthcare scenario and paving the way for more effective clinical research and data-driven decision-making.

Verapamil increases susceptibility of colistin-resistant Acinetobacter baumannii to colistin.

Acinetobacter baumannii, which is predominantly responsible for hospital-acquired infections, presents a tremendous clinical challenge due to its increasing antibiotic resistance to colistin (COL), a last-line antibiotic. As a result, the combination of antimicrobial and non-antimicrobial agents is emerging as a more popular treatment approach against infections caused by COL-resistant A. baumannii. This study administered COL and verapamil (VER), that is an antihypertensive and antiarrhythmic agent. We found that the susceptibility of A. baumannii to COL was restored both in vitro and in vivo. Scanning electron microscope and Crystal violet staining showed inhibition of the VER/COL combination on bacterial biofilm formation. Cytotoxicity assay and haemolysis test were used to confirm in vitro safety evaluation. Further experiments using propidium iodide staining revealed that the VER/COL combination improved the therapeutic efficacy of COL by modifying the permeability of bacterial membranes. As demonstrated by reactive oxygen species experiments, the drug combination caused the accumulation of bacterial reactive oxygen species and their eventual death. Additionally, VER/COL treatment significantly reduced the efflux of Rhodamine 123 (Rh123). For the first time, this study identifies the anti-hypertensive drug VER as a COL potentiator against A. baumannii, providing a potential treatment approach against A. baumannii infections and improving patient outcomes.

MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation.

Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1f/fMb1Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.

Pathway of Effects of Socioeconomic Status on Rural Left-behind Children to Receive Oral Health Services: A Structural Equation Modeling.

In a rural area with a high proportion of left-behind children (LBC), we aimed to identify the pathway of influence of socioeconomic status (SES) on LBCs to receive oral health services after individualized advice. Between September and October 2020, in a rural area of Yunnan, a survey of 238 LBC and 210 non-left-behind children (NLBC) showed that 91.9% and 94.2% had primary teeth caries, respectively. Their caregivers were advised on (1) dental care: bringing the children to seek professional dental care; and (2) self-care: supervising the children's oral health behaviors. Two to three months later, the children and their caregivers were visited to assess the compliance with these items of advice. Structural equation modeling (SEM) was used to handle the association between SES and compliance with the advice. A heatmap was used to visualize the data of reasons for seeking dental care or not. A total of 183 (87.1%) NLBCs and 206 (86.6%) LBCs were given the above advice; 32.9% of caregivers complied with dental care advice without a statistical difference between the LBC and NLBC group; 69.9% of caregivers of NLBCs complied with self-care advice, statistically more than those LBCs (59.2%). The education of caregivers was significantly associated with compliance with both advice items in univariate analysis. SES had a direct effect on the children being left behind and the level of oral health knowledge and awareness of the caregivers. Being left behind did not have an independent effect on receiving oral health services for children. "Dental disease was not severe" and "having no pain" were the main reasons for not seeking dental care. There was no clear grouping of participants with different background information based on the reasons given for seeking or not seeking dental care. Our study pointed to the importance of SES level. Being left behind alone may not be a risk factor for missing oral health services among rural children.