Background Cryptococcal meningitis is characterized by prominent neuroinflammation, with microglia and astrocytes being the primary glial cells involved in this process. However, the molecular mechanisms underlying the microglia-astrocyte interactions mediated by extracellular vesicles (EVs) during cryptococcal infection have not yet been fully elucidated. Methods We treated human HMC3 microglia with heat-killed Cryptococcus neoformans (strain WM148) and purified EVs via ultracentrifugation. EV morphology and markers were assessed by TEM, NTA, and Western blot. Dye-labeled EV uptake by HA1800 astrocytes was assessed by confocal microscopy. Functional effects on astrocytes were evaluated using CCK-8, Annexin V/PI staining, ELISA, RT-qPCR, and Western blotting. miRNA sequencing identified differentially expressed miRNAs, and mechanistic studies were performed using miRNA inhibition, luciferase reporter assays, and gene silencing. Results Our findings show that astrocytes internalize morphologically intact EVs derived from HMC3/WM148. EV uptake reduces astrocyte viability, induces apoptosis, and increases secretion of IL-1β, IL-6 and TNF-α. GW4869-mediated inhibition of EV biogenesis largely reverses these harmful effects. miRNA profiling identifies high enrichment of miR-196b-5p in EVs. Functional assays verify miR-196b-5p as a pro-inflammatory mediator; its inhibition rescues astrocyte apoptosis and cytokine release. Mechanistically, miR-196b-5p directly targets FAS in HEK293T. Consistently, FAS knockdown abrogates the protective effect of miR-196b-5p inhibition in HA1800 astrocytes. Conclusions Cryptococcus neoformans stimulate reprograms microglial-derived EVs to promote astrocyte inflammation and injury through the miR-196b-5p-FAS axis. These findings identify the EV-associated miR-196b-5p/FAS axis as a candidate mechanism of glial inflammatory communication that warrants validation in primary-cell, live-infection, and in-vivo models.
This paper introduces improved logarithmic type estimator to estimate the finite population distribution function (DF) using two auxiliary variables. The proposed estimator aims to make better use of the auxiliary information than the existing estimators, for better estimation precision. The use of a logarithmic functional form is used to make the estimator efficient when the auxiliary variables are correlated with the study variable. First-order approximation is used to derive the statistical properties such as bias and the mean squared error. Theoretical efficiency conditions are obtained that characterize conditions under which the proposed estimator is more efficient than some of the other estimators of the population DF. Empirical studies are carried out with actual data on cultural communication and radiation sciences to evaluate the practical performance. The numerical results show that the proposed estimator has the lowest MSE and the highest PREs than the other competing estimators in study. The results indicate that the simultaneous application of two related auxiliary variables can yield significant gains in the accuracy of the estimation of the population DF. Hence the proposed approach offers a generally applicable and efficient framework for finite population inference and might be especially suitable in applications for which reliable auxiliary information is easily available, such as cultural, communication, environmental, medical, and radiation-related studies.
This paper investigated the development of flexible polyvinyl chloride (PVC)-based composites reinforced with heavy metal oxides, including CuO, WO 3 , and Bi 2 O 3 , to improve gamma-ray shielding efficiency of PVC-compound. Four composites were prepared at different weight ratios, including a pure sample (PVC-0) and other loaded with oxides based on oxides ratio. Experimental measurements were performed using radiation sources at different energies, with calculations of linear attenuation coefficients (LAC) and shielding efficiency. Theoretical calculations were also performed using XCOM software for comparison with the experimental results. The results showed good agreement between the experimental and theoretical values. The LAC values at 0.0595 MeV were 0.442, 2.406, 3.500, and 3.280 cm −1 , while at 0.6617 MeV they were 0.104, 0.160, 0.172, and 0.173 cm −1 for PVC-0, PVC-1, PVC-2, and PVC-3, respectively. The results showed that the addition of heavy oxides significantly improved the attenuation properties compared to the pure sample, with a synergistic effect observed in hybrid formulations containing more than one type of oxide. The developed composites exhibit a suitable balance between flexibility and shielding efficiency, making them suitable candidates for use in lightweight and flexible radiation shielding applications.
This paper investigated the development of flexible polyvinyl chloride (PVC)-based composites reinforced with heavy metal oxides, including CuO, WO3, and Bi2O3, to improve gamma-ray shielding efficiency of PVC-compound. Four composites were prepared at different weight ratios, including a pure sample (PVC-0) and other loaded with oxides based on oxides ratio. Experimental measurements were performed using radiation sources at different energies, with calculations of linear attenuation coefficients (LAC) and shielding efficiency. Theoretical calculations were also performed using XCOM software for comparison with the experimental results. The results showed good agreement between the experimental and theoretical values. The LAC values at 0.0595 MeV were 0.442, 2.406, 3.500, and 3.280 cm−1, while at 0.6617 MeV they were 0.104, 0.160, 0.172, and 0.173 cm−1 for PVC-0, PVC-1, PVC-2, and PVC-3, respectively. The results showed that the addition of heavy oxides significantly improved the attenuation properties compared to the pure sample, with a synergistic effect observed in hybrid formulations containing more than one type of oxide. The developed composites exhibit a suitable balance between flexibility and shielding efficiency, making them suitable candidates for use in lightweight and flexible radiation shielding applications.
Background: Cisplatin resistance is a problem for the clinical treatment of ovarian cancer. The basic path by which cancer-secreted exosomal PD-L1 modifies the immune environment to promote chemoresistance is not known. This study investigated how ovarian carcinoma exosomal PD-L1 promotes CD8 + T cell dysfunction and cisplatin resistance. Methods: SKOV3-originating exosomes were used to study uptake by CD8 + T cells, PD-1 expression, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, and dysfunction markers, both in the presence and absence of exosomal PD-L1 silencing. Mice bearing tumours were treated in vivo with either cisplatin alone or in combination with SKOV3 exosomes/shPD-L1 exosomes, and then tumour expansion, cisplatin efficacy, exhausted T cell ratios and PI3K/AKT/mTOR activation in isolated tumour CD8 + T cells were assessed. Results: Ovarian cancer-derived vesicles carrying PD-L1 were taken up by CD8 + T cells and were associated with increased PD-1 expression and impaired effector function. In vitro, SKOV3-derived vesicles increased cisplatin tolerance in SKOV3 cells, whereas in the xenograft experiment they were associated with reduced cisplatin tumor-growth inhibition; both effects were attenuated when vesicles were derived from PD-L1-silenced cells. The exosome group had more exhausted T cells, and tumor-derived CD8 + T cells showed reduced PI3K/AKT/mTOR signalling; shPD-L1 restored this signalisation. The study demonstrates parallel associations of SKOV3-derived vesicles with CD8 + T-cell dysfunction and tumor-cell cisplatin tolerance; it does not establish that the immune phenotype causes the tumor-cell-autonomous resistance observed in vitro. Conclusion: ovarian cancer exosomes deliver PD-L1 to tumour-resident CD8 + T cells, inhibit the PI3K/AKT/mTOR pathway to induce T cell dysfunction, thereby fostering an immunosuppressive microenvironment that supports cisplatin resistance. These preclinical findings identify exosomal PD-L1 as a candidate contributor to CD8 + T-cell dysfunction and reduced cisplatin sensitivity, warranting validation in immunocompetent or humanized models and patient-derived samples.
