Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway-mediated neuroinflammation in db/db mice.

Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1ß, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.

Dysrhythmic saliva microbiota in mobile phone addicts with sleep disorders and restored by acupuncture.

Background: Mobile phone addiction (MPA) greatly affects the biological clock and sleep quality and is emerging as a behavioral disorder. The saliva microbiota has been linked to circadian rhythms, and our previous research revealed dysrhythmic saliva metabolites in MPA subjects with sleep disorders (MPASD). In addition, acupuncture had positive effects. However, the dysbiotic saliva microbiota in MPASD patients and the restorative effects of acupuncture are unclear. Objectives: To probe the circadian dysrhythmic characteristics of the saliva microbiota and acupunctural restoration in MPASD patients. Methods: MPASD patients and healthy volunteers were recruited by the Mobile Phone Addiction Tendency Scale (MPATS) and the Pittsburgh Sleep Quality Index (PSQI). Saliva samples were collected every 4 h for 72 h. After saliva sampling, six MPDSD subjects (group M) were acupuncturally treated (group T), and subsequent saliva sampling was conducted posttreatment. Finally, all the samples were subjected to 16S rRNA gene sequencing and bioinformatic analysis. Results: Significantly increased MPATS and PSQI scores were observed in MPDSD patients (p< 0.01), but these scores decreased (p<0.001) after acupuncture intervention. Compared with those in healthy controls, the diversity and structure of the saliva microbiota in MPASD patients were markedly disrupted. Six genera with circadian rhythms were detected in all groups, including Sulfurovum, Peptostreptococcus, Porphyromonas and Prevotella. There were five genera with circadian rhythmicity in healthy people, of which the rhythmicities of the genera Rothia and Lautropia disappeared in MPASD patients but effectively resumed after acupuncture intervention. Conclusions: This work revealed dysrhythmic salivary microbes in MPASD patients, and acupuncture, as a potential intervention, could be effective in mitigating this ever-rising behavioral epidemic.

Phosphonium Iodide Featuring Blue Thermally Activated Delayed Fluorescence for Highly Efficient X-ray Scintillator.

Organic scintillators are praised for their abundant element reserves, facile preparation procedures, and rich structures. Herein, a new family of highly efficient organic phosphonium halide salts with thermally activated delayed fluorescence (TADF) are designed by innovatively adopting quaternary phosphonium as the electron acceptor, while dimethylamine group and halide anions (I-) serve as the electron donor. The prepared butyl(2-[2-(dimethylamino)phenyl]phenyl)diphenylphosphonium iodide (C4-I) exhibits bright blue emission and an ultra-high photoluminescence quantum yield (PLQY) of 100%. Efficient charge transfer is realized through the unique n-π and anion-π stacking in solid-state C4-I. Photophysical studies of C4-I suggest that the incorporation of I accounts for high intersystem crossing rate (kISC) and reverse intersystem crossing rate (kRISC), suppressing the intrinsic prompt fluorescence and enabling near-pure TADF emission at room temperature. Benefitting from the large Stokes shift, high PLQY, efficient exciton utilization, and remarkable X-ray attenuation ability endowed by I, C4-I delivers an outstanding light yield of 80721 photons/MeV and a low limit of detection (LoD) of 22.79 nGy·s-1. This work would provide a rational design concept and open up an appealing road for developing efficient organic scintillators with tunable emission, strong X-ray attenuation ability, and excellent scintillator performance.

[Hypothetical Alcohol Consumption Interventions and Hepatic Steatosis: A Longitudinal Study in a Large Cohort]. / æ¨¡æ‹Ÿé¥®é ’å¹²é¢„ä¸Žè‚è„‚è‚ªå˜æ€§ï¼šä¸€é¡¹å¤§åž‹é˜Ÿåˆ—çš„çºµå‘ç ”ç©¶.

Objective: Non-alcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (ALD) are the most common chronic liver diseases. Hepatic steatosis is an early histological subtype of both NAFLD and ALD. Excessive alcohol consumption is widely known to lead to hepatic steatosis and subsequent liver damage. However, reported findings concerning the association between moderate alcohol consumption and hepatic steatosis remain inconsistent. Notably, alcohol consumption as a modifiable lifestyle behavior is likely to change over time, but most previous studies covered alcohol intake only once at baseline. These inconsistent findings from existing studies do not inform decision-making concerning policies and clinical guidelines, which are of greater interest to health policymakers and clinician-scientists. Additionally, recommendations on the types of alcoholic beverages are not available. Usually, assessing the effects of two or more hypothetical alcohol consumption interventions on hepatic steatosis provides answers to questions concerning the population risk of hepatic steatosis if everyone changes from heavy drinking to abstinence, or if everyone keeps on drinking moderately, or if everyone of the drinking population switches from red wine to beer? Thus, we simulated a target trial to estimate the effects of several hypothetical interventions, including changes in the amount of alcohol consumption or the types of alcoholic beverages consumed, on hepatic steatosis using longitudinal data, to inform decisions about alcohol-related policymaking and clinical care. Methods: This longitudinal study included 12687 participants from the UK Biobank (UKB), all of whom participated in both baseline and repeat surveys. We excluded participants with missing data related to components of alcohol consumption and fatty liver index (FLI) in the baseline and the repeat surveys, as well as those who had reported liver diseases or cancer at the baseline survey. We used FLI as an outcome indicator and divided the participants into non-, moderate, and heavy drinkers. The surrogate marker FLI has been endorsed by many international organizations' guidelines, such as the European Association for the Study of the Liver. The calculation of FLI was based on laboratory and anthropometric data, including triglyceride, gamma-glutamyl transferase, body mass index, and waist circumference. Participants responded to questions about the types of alcoholic beverages, which were defined in 5 categories, including red wine, white wine/fortified wine/champagne, beer or cider, spirits, and mixed liqueurs, along with the average weekly or monthly amounts of alcohol consumed. Alcohol consumption was defined as pure alcohol consumed per week and was calculated according to the amount of alcoholic beverages consumed per week and the average ethanol content by volume in each alcoholic beverage. Participants were categorized as non-drinkers, moderate drinkers, and heavy drinkers according to the amount of their alcohol consumption. Moderate drinking was defined as consuming no more than 210 g of alcohol per week for men and 140 g of alcohol per week for women. We defined the following hypothetical interventions for the amount of alcohol consumed: sustaining a certain level of alcohol consumption from baseline to the repeat survey (e.g., none to none, moderate to moderate, heavy to heavy) and changing from one alcohol consumption level to another (e.g., none to moderate, moderate to heavy). The hypothetical interventions for the types of alcoholic beverages were defined in a similar way to those for the amount of alcohol consumed (e.g., red wine to red wine, red wine to beer/cider). We applied the parametric g-formula to estimate the effect of each hypothetical alcohol consumption intervention on the FLI. To implement the parametric g-formula, we first modeled the probability of time-varying confounders and FLI conditional on covariates. We then used these conditional probabilities to estimate the FLI value if the alcohol consumption level of each participant was under a specific hypothetical intervention. The confidence interval was obtained by 200 bootstrap samples. Results: For the alcohol consumption from baseline to the repeat surveys, 6.65% of the participants were sustained non-drinkers, 63.68% were sustained moderate drinkers, and 14.74% were sustained heavy drinkers, while 8.39% changed from heavy drinking to moderate drinking. Regarding the types of alcoholic beverages from baseline to the repeat surveys, 27.06% of the drinkers sustained their intake of red wine. Whatever the baseline alcohol consumption level, the hypothetical interventions for increasing alcohol consumption from the baseline alcohol consumption were associated with a higher FLI than that of the sustained baseline alcohol consumption level. When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to moderate drinking, the mean ratio of FLI was 1.027 (95% confidence interval [CI]: 0.997-1.057). When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to heavy drinking, the mean ratio of FLI was 1.075 (95% CI: 1.042-1.108). When comparing sustained heavy drinking with the hypothetical intervention of changing from heavy drinking to moderate drinking, the mean ratio of FLI was 0.953 (95% CI: 0.938-0.968). The hypothetical intervention of changing to red wine in the UKB was associated with lower FLI levels, compared with sustained consumption of other types of alcoholic beverages. For example, when comparing sustaining spirits with the hypothetical intervention of changing from spirits to red wine, the mean ratio of FLI was 0.981 (95% CI: 0.948-1.014). Conclusions: Regardless of the current level of alcohol consumption, interventions that increase alcohol consumption could raise the risk of hepatic steatosis in Western populations. The findings of this study could inform the formulation of future practice guidelines and health policies. If quitting drinking is challenging, red wine may be a better option than other types of alcoholic beverages in Western populations.

STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma.

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.

A fast and sensitive size-exclusion chromatography method for plasma extracellular vesicle proteomic analysis.

Extracellular vesicles (EVs) carry diverse biomolecules derived from their parental cells, making their components excellent biomarker candidates. However, purifying EVs is a major hurdle in biomarker discovery since current methods require large amounts of samples, are time-consuming and typically have poor reproducibility. Here we describe a simple, fast, and sensitive EV fractionation method using size exclusion chromatography (SEC) on a fast protein liquid chromatography (FPLC) system. Our method uses a Superose 6 Increase 5/150, which has a bed volume of 2.9 mL. The FPLC system and small column size enable reproducible separation of only 50 µL of human plasma in 15 min. To demonstrate the utility of our method, we used longitudinal samples from a group of individuals who underwent intense exercise. A total of 838 proteins were identified, of which, 261 were previously characterized as EV proteins, including classical markers, such as cluster of differentiation (CD)9 and CD81. Quantitative analysis showed low technical variability with correlation coefficients greater than 0.9 between replicates. The analysis captured differences in relevant EV proteins involved in response to physical activity. Our method enables fast and sensitive fractionation of plasma EVs with low variability, which will facilitate biomarker studies in large clinical cohorts.

The effects of nutrition education on nutritional knowledge and dietary behaviours in primary school students in Zhongshan city.

BACKGROUND: Adequate nutritional knowledge and healthy dietary behaviours are essential for promoting rational nutrition for children. However, lack of nutritional knowledge and unhealthy dietary behaviours are common among Chinese children. Therefore, we developed a school-based nutrition education (NE) program to assess its impacts on nutritional knowledge and dietary behaviours in pupils. METHODS: In this trial, one school was assigned as an intervention group (n = 199) and the other two schools were designated as a control group (n = 140). Children in the intervention group received the NE program in addition to their regular health curriculum, whereas the control group continued with their usual health curriculum without any NE program materials. RESULTS: Concerning nutritional knowledge, the mean difference (follow-up minus baseline) of average knowledge scores in the intervention group was significantly higher than that in the control group (1.99 ± 3.22 vs. 0.66 ± 3.60, p = 0.001). However, subgroup analysis revealed that this difference disappeared among boys and students with malnutrition status. Regarding dietary behaviours, the NE program significantly increased the proportion of children exhibiting high frequencies of meat and nuts consumption in the intervention group, along with diverse food choice at breakfast. Additionally, it markedly reduced the proportion of children exhibiting high frequencies of sugar-sweetened beverages and fast food consumption. Structural equation modelling analyses indicated a significant direct effect of NE intervention on nutritional knowledge and an indirect effect on dietary behaviours. CONCLUSIONS: The NE program effectively enhanced nutritional knowledge scores and further improved dietary behaviours among Chinese primary school students. Future NE programs should pay more attention to boys and children with malnutrition.

Red Blood Cell-Hitchhiking Delivery of Simvastatin to Relieve Acute Respiratory Distress Syndrome.

Purpose: The purpose of this study is to address the high mortality and poor prognosis associated with Acute Respiratory Distress Syndrome (ARDS), conditions characterized by acute and progressive respiratory failure. The primary goal was to prolong drug circulation time, increase drug accumulation in the lungs, and minimize drug-related side effects. Methods: Simvastatin (SIM) was used as the model drug in this study. Employing a red blood cell surface-loaded nanoparticle drug delivery technique, pH-responsive cationic nanoparticles loaded with SIM were non-covalently adsorbed onto the surface of red blood cells (RBC), creating a novel drug delivery system (RBC@SIM-PEI-PPNPs). Results: The RBC@SIM-PEI-PPNPs delivery system effectively extended the drug's circulation time, providing an extended therapeutic window. Additionally, this method substantially improved the targeted accumulation of SIM in lung tissues, thereby enhancing the drug's efficacy in treating ARDS and impeding its progression to ARDS. Crucially, the system showed a reduced risk of adverse drug reactions. Conclusion: RBC@SIM-PEI-PPNPs demonstrates promise in ARDS and ARDS treatment. This innovative approach successfully overcomes the limitations associated with SIM's poor solubility and low bioavailability, resulting in improved therapeutic outcomes and fewer drug-related side effects. This research holds significant clinical implications and highlights its potential for broader application in drug delivery and lung disease treatment.

Free-space coupled, large-active-area superconducting microstrip single-photon detector for photon-counting time-of-flight imaging.

Numerous applications at the photon-starved regime require a free-space coupling single-photon detector with a large active area, low dark count rate (DCR), and superior time resolutions. Here, we developed a superconducting microstrip single-photon detector (SMSPD), with a large active area of 260 µm in diameter, a DCR of ∼5k c p s, and a low time jitter of ∼171p s, operated at a near-infrared of 1550 nm and a temperature of ∼2.0K. As a demonstration, we applied the detector to a single-pixel galvanometer scanning system and successfully reconstructed the object information in depth and intensity using a time-correlated photon counting technology.

Discriminating atypical parotid carcinoma and pleomorphic adenoma utilizing extracellular volume fraction and arterial enhancement fraction derived from contrast-enhanced CT imaging: A multicenter study.

OBJECTIVES: To investigate the added value of extracellular volume fraction (ECV) and arterial enhancement fraction (AEF) derived from enhanced CT to conventional image and clinical features for differentiating between pleomorphic adenoma (PA) and atypical parotid adenocarcinoma (PCA) pre-operation. METHODS: From January 2010 to October 2023, a total of 187 cases of parotid tumors were recruited, and divided into training cohort (102 PAs and 51 PCAs) and testing cohort (24 PAs and 10 atypical PCAs). Clinical and CT image features of tumor were assessed. Both enhanced CT-derived ECV and AEF were calculated. Univariate analysis identified variables with statistically significant differences between the two subgroups in the training cohort. Multivariate logistic regression analysis with the forward variable selection method was used to build four models (clinical model, clinical model+ECV, clinical model+AEF, and combined model). Diagnostic performances were evaluated using receiver operating characteristic (ROC) curve analyses. Delong's test compared model differences, and calibration curve and decision curve analysis (DCA) assessed calibration and clinical application. RESULTS: Age and boundary were chosen to build clinical model, and to construct its ROC curve. Amalgamating the clinical model, ECV, and AEF to establish a combined model demonstrated superior diagnostic effectiveness compared to the clinical model in both the training and test cohorts (AUC = 0.888, 0.867). There was a significant statistical difference between the combined model and the clinical model in the training cohort (p = 0.0145). CONCLUSIONS: ECV and AEF are helpful in differentiating PA and atypical PCA, and integrating clinical and CT image features can further improve the diagnostic performance.

Population pharmacokinetics of valproic acid in children with epilepsy: Implications for dose tailoring when switching from oral syrup to sustained-release tablets.

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h-1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

Single-cell transcriptomic analysis of the immune microenvironment in pediatric acute leukemia.

Relapse and treatment resistance pose significant challenges in the management of pediatric B cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML). The efficacy of immunotherapy in leukemia remains limited due to factors such as the immunosuppressive tumor microenvironment (TME) and lack of suitable immunotherapeutic targets. Thus, an in-depth characterization of the TME in pediatric leukemia is warranted to improve the efficacy of immunotherapy. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the TME of pediatric B-ALL and AML, focusing specifically on bone-marrow-derived T cells. Moreover, we investigated the transcriptome changes during the initiation, remission, and relapse stages of pediatric AML. Our findings revealed that specific functional expression programs correlated with fluctuations in various T cell subsets, which may be associated with AML progression and relapse. Furthermore, our analysis of cellular communication networks led to the identification of VISTA, CD244, and TIM3 as potential immunotherapeutic targets in pediatric AML. Finally, we detected elevated proportions of γδ T cells and associated functional genes in samples from pediatric patients diagnosed with B-ALL and AML, which could inform the development of novel therapeutic approaches, potentially focusing on γδ T cells.

Development of SPEEK-Coated IrOx Sensor for High-Biomass Aquatic pH Monitoring.

Instability is a key challenge for current pH sensors in practical applications, especially in aquatic environments with high biomass and redox substances. Herein, we present a novel approach that uses a highly stable IrOx sensing layer enveloped in a composite film of SPEEK doped with a silicon-stabilized ionic liquid (SP-IrOx). This design mitigates drift due to sensitive layer variations and minimizes interference from complex external conditions. After exhibiting robustness under moderately reducing conditions caused by S2-, I-, and ascorbic acid, the SP-IrOx sensor's efficacy was validated through real-time pH measurements in demanding aquatic settings. These included laboratory algal culture medium, sediment substrates, and mussel aquaculture areas. The sensor sustained accuracy and stability over extended periods of 6-8 days when compared to calibrated commercial electrodes. The deviations from reference samples were minimal, with a variance of no more than 0.03 pH units in mussel aquaculture areas (n = 17) and 0.07 pH units in an algal culture medium (n = 37). As a potentiometric, this solid-state electrode features a compact structure and low energy consumption, making it an economical and low-maintenance solution for precise pH monitoring in diverse challenging environments with high biomass and turbidity.

[The Preventive Effect of Levofloxacin Combined with G-CSF or Only G-CSF Supportive Therapy on Infection in Autologous Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To investigate the role of levofloxacin combined with recombinant human granulocyte colony-stimulating factor (G-CSF) or only G-CSF supportive therapy in preventing infection in autologous hematopoietic stem cell transplantation(ASCT), and to analyze the length of hospital stay, hospitalization cost and post-transplant survival of the patients. METHODS: A retrospective analysis was performed in the patients with hematological malignancies who accepted ASCT at our hospital from January 2012 to July 2022, the febrile neutropenia, the incidence of bacterial infection and the use rate of intravenous antibiotics in the levofloxacin+G-CSF group and only G-CSF support group during ASCT were observed. The length of hospital stay, total cost during hospitalization and survival after 90 days of transplantation between the two groups were compared. RESULTS: A total of 102 cases were included in this study, including 57 cases of multiple myeloma, 36 cases of acute leukaemia, 7 cases of lymphoma, 3 cases of myelodysplastic syndrome, 1 case of light chain amyloidosis, and 1 case of POEMS syndrome. 47 patients received levofloxacin+ G-CSF antibacterial prophylaxis, and 55 patients received G-CSF supportive therapy. In the levofloxacin+ G-CSF group, 40 cases (85.11%) developed febrile neutropenia, and 13 cases (27.66%) were confirmed as bacterial infection. In the G-CSF group, 44 cases (80.00%) developed febrile neutropenia, and 16 cases (29.09%) were bacterial infection. There was no statistically significant difference in the incidence of febrile neutropenia and bacterial infection between the two groups (χ2=0.46，P =0.50; χ2=0.03，P =0.87). The use rate of intravenous antibiotics in the levofloxacin+ G-CSF group was 85.11% (40/47), which was not statistically different from 85.45% (47/55) in the G-CSF group (χ2=0.04，P =0.84). The detection rates of levofloxacin-resistant bacteria in the levofloxacin+ G-CSF group and G-CSF group were 8.57% (3/35) and 21.43% (6/28), respectively, with no statistical difference (χ2=0.65, P >0.05). The median length and median cost of hospitalization in the levofloxacin+ G-CSF group and G-CSF group were 25 d vs 22 d and 78 216.24 yuan vs 80 724.38 yuan, with no statistically significant differences ( t =3.00，P =0.09; t =0.94，P =0.09). Within 90 days after transplantation, two cases (4.26%) died in the levofloxacin+ G-CSF group and one case (1.82%) died in the G-CSF group, with no statistically significant difference between the two groups (χ2=0.53，P =0.47). CONCLUSION: Application of levofloxacin+ G-CSF showed no significant benefit compared to G-CSF support for the prevention of bacterial infections during ASCT.

Increased Generalization, Stronger Acquisition, or Reduced Extinction? Investigation of the Mechanisms Underlying the Acquisition-in-Multiple-Contexts Effect.

Prior research has demonstrated that conducting acquisition in multiple contexts results in more responding to the point that it can even nullify the benefit of subsequent extinction in multiple contexts on reducing renewal of excitatory responding. The underlying mechanism to explain why this happens has not been systematically examined. Using self-reported expectancy of the outcome, the current study investigates three mechanisms that potentially explain why acquisition in multiple contexts results in more responding-greater generalization, stronger acquisition learning, or slower extinction learning. Participants (N = 180) received discriminative training with a conditioned stimulus (CS+) and outcome pairing and a CS- → noOutcome pairing in either one or three contexts. This was followed by either extinction treatment in a novel context or no extinction. Finally, testing occurred in the acquisition context, the extinction context, or a novel context. Stronger renewal of extinguished conditioned expectation was observed for participants who received CS+ → Outcome pairings in three contexts relative to one context. There was no effect of the number of contexts on the strength of the excitatory CS+ → Outcome association or degree of inhibitory learning that occurred during extinction. This suggests that generalization is the mechanism responsible for the adverse impact to extinction learning when acquisition is conducted in multiple contexts.

The impact of family socioeconomic status on parental involvement and student engagement during COVID-19 in promoting academic achievement: A longitudinal study in Chinese children.

With a three-wave longitudinal design, the current study examined the impact of family socioeconomic status (SES) on parental involvement and student engagement in promoting children's academic achievement during the coronavirus disease 2019 (COVID-19) pandemic. We recruited data from 246 mother-primary school student dyads, and the mean age of children at Wave 1 was 10.57 ± 0.97 years (range = 9-13 years). The academic achievement of these children was measured both before and after school closures. Family SES, parental involvement, and student engagement were assessed during the school closures. The results indicated that family SES could predict children's later academic achievement after accounting for their prior academic achievement and other demographics (i.e., the significant total effect in the model). Moreover, parental involvement and student engagement played chain-mediating roles in the effect of family SES on children's later academic achievement. Neither parent involvement nor student involvement alone mediated the relationships between family SES and subsequent academic achievement. Suggestions are provided to minimize the negative impact of low family SES on children's academic achievement during pandemics.

Contrast-enhanced Imaging in Peripheral Pulmonary Lesions: The Role in US-guided Biopsies.

Purpose To compare the tissue adequacy and diagnostic accuracy of US-guided biopsies of peripheral pulmonary lesions (PPLs) with and without contrast agents. Materials and Methods A retrospective study was conducted at four medical centers in patients with PPLs who underwent US-guided percutaneous transthoracic needle biopsy (PTNB) between January 2017 and October 2022. The patients were divided into contrast-enhanced US (CEUS) and US groups based on whether prebiopsy CEUS evaluation was performed. Tissue adequacy and the diagnostic accuracy of PTNB, stratified by lesion size, were analyzed and compared between groups. A propensity score matching (PSM) analysis was conducted using the nearest-neighbor matching method. Results A total of 1027 lesions were analyzed, with 634 patients (mean age, 59.4 years ± 13.0 [SD]; 413 male) in the US group and 393 patients (mean age, 61.2 years ± 12.5; 270 male) in the CEUS group. The CEUS group produced more acceptable samples than the US group (98.2% vs 95.7%; P = .03) and achieved higher diagnostic accuracy (96.9% vs 94.2%; P = .04), with no evidence of a difference in sensitivity (96.7% vs 94.0%; P = .06). PSM and stratified analyses (n = 358 per group) indicated higher tissue adequacy (99.0% vs 95.7%; P = .04) and diagnostic accuracy (98.5% vs 92.9%; P = .006) in the CEUS group compared with the US group for 2-7-cm PPLs but not for lesions larger than 7 cm. Conclusion PTNB with prebiopsy CEUS evaluation demonstrated significantly better tissue adequacy and diagnostic accuracy compared with US guidance alone for PPLs ranging from 2 to 7 cm, with similar biopsy performance achieved between groups for lesions larger than 7 cm. Keywords: Contrast Material, Thoracic Diseases, Ultrasonography, Image-Guided Biopsy © RSNA, 2024.

A novel treatment modality for rheumatoid arthritis: Inflammation-targeted multifunctional metal-organic frameworks with synergistic phototherapy and chemotherapy.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex pathogenesis. Single chemotherapy struggles to eliminate the disease permanently and reduce the pain owing to drug resistance and inadequate delivery to target cells. This study developed hyaluronic acid (HA)-modified and methotrexate (MTX)-load metal-organic frameworks (denoted as FT-HA-MTX NPs), combining photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy to inhibit the progression of RA. In vitro experiments proved that the obtained NPs exhibited good biocompatibility and commendable photothermal conversion efficiency of 36.3 %. Additionally, they promoted ∙OH and O2 production via the Fenton reaction, which dramatically alleviated hypoxia and enhanced ROS generation, and induced substantial mortality in activated RAW 264.7 cells, with cell viability of 31.72 %. Cellular uptake and in vivo imaging confirmed that the modification of HA enabled the NPs to specifically target activated macrophage, ensured prolonged retention of NPs in inflamed synovial tissues, and reduced systemic toxicity. In vivo, after FT-HA-MTX NPs treatment with laser irradiation, the levels of TNF-α and IL-1ß in the synovial tissue were reduced by approximately 50 % compared to those in the inflamed synovium, demonstrating a significant enhancement in the anti-inflammatory effect (p < 0.001). In conclusion, FT-HA-MTX NPs are promising inflammation-targeted multifunctional nanoparticles that combine PTT, PDT, and chemotherapy, thereby significantly inhibiting the progression of RA while reducing systemic toxicity.

Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

Hexagonal Bipyramidal Mn3Ge5 Cluster and Its One-Dimensional Ferrimagnetic Sandwich Nanowire: Mn3Ge3 Rings as Structural Motifs.

Bipyramidal structures featuring planar rings serve as potential building blocks for one-dimensional (1D) nanostructures. Pure Ge atoms typically prefer to form three-dimensional rather than planar structures. Although a few-metal-doped bipyramids with pure Ge planar rings are predicted for constructing Ge-based 1D nanostructures, there is limited knowledge about those with both Ge and doped atoms on the same planar rings. Here, we report a hexagonal bipyramidal Mn3Ge5 cluster containing a Mn3Ge3 six-membered ring with the potential to construct a 1D germanium-based nanostructure. We investigated the structures and properties of Mn3Ge5-/0 using anion photoelectron spectroscopy and theoretical calculations. Mn3Ge5- has a C3v symmetric distorted hexagonal bipyramidal structure, while Mn3Ge5 has a C2v symmetric hexagonal bipyramidal structure. Chemical bonding analyses show that Mn3Ge5- could be considered as a [Mn3]V[Ge5]6- complex. First-principles calculations indicate that Mn3Ge5 may be used to construct a 1D ferrimagnetic [Mn3Ge5]∞ nanostructure.