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Streptococcus pneumoniae, a common cause of community-acquired bacterial pneumonia, can cross the respiratory epithelial barrier to cause lethal septicemia and meningitis. S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers robust neutrophil (PMN) infiltration that promotes bacterial transepithelial migration in vitro and disseminated disease in mice. Apical infection of polarized respiratory epithelial monolayers by S. pneumoniae at a multiplicity of infection (MOI) of 20 resulted in recruitment of PMNs, loss of 50% of the monolayer, and PMN-dependent bacterial translocation. Reducing the MOI to 2 decreased PMN recruitment two-fold and preserved the monolayer, but apical-to-basolateral translocation of S. pneumoniae remained relatively efficient. At both MOI of 2 and 20, PLY was required for maximal PMN recruitment and bacterial translocation. Co-infection by wild-type S. pneumoniae restored translocation by a PLY-deficient mutant, indicating that PLY can act in trans. Investigating the contribution of S. pneumoniae infection on apical junction complexes in the absence of PMN transmigration, we found that S. pneumoniae infection triggered the cleavage and mislocalization of the adherens junction (AJ) protein E-cadherin. This disruption was PLY-dependent at MOI of 2 and was recapitulated by purified PLY, requiring its pore-forming activity. In contrast, at MOI of 20, E-cadherin disruption was independent of PLY, indicating that S. pneumoniae encodes multiple means to disrupt epithelial integrity. This disruption was insufficient to promote bacterial translocation in the absence of PMNs. Thus, S. pneumoniae triggers cleavage and mislocalization of E-cadherin through PLY-dependent and -independent mechanisms, but maximal bacterial translocation across epithelial monolayers requires PLY-dependent neutrophil transmigration.

Internet addiction has rapidly become a prevalent concern among left-behind children in China. Using the hierarchical multiple regression analysis, this cross-sectional study aims to investigate the correlation among loneliness, psychological resilience, and Internet addiction, as well as determine whether the adverse impact of loneliness could be buffered by psychological resilience. The findings revealed that loneliness positively correlated with Internet addiction, while psychological resilience negatively correlated with Internet addiction. The moderating effect analysis suggested that resilience could alleviate the adverse impact of loneliness on Internet addiction. Specifically, a statistically significantly positive effect of loneliness was noted on Internet addiction among children with low resilience, whereas no significant association between loneliness and Internet addiction was found among those with a high level of resilience. In conclusion, this study sheds light on the psychosocial mechanisms how loneliness might affect Internet addiction among left-behind children in China., Author(s): Qilong Cao [sup.1] , Jing An [sup.2] , Yizhu Yang [sup.1] , Peiyun Peng [sup.1] , Shuying Xu [sup.1] , Xiao Xu [sup.1] , Hongjie Xiang [sup.1] Author Affiliations: [...]

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG tract expansion in the huntingtin gene (HTT). HD is characterized by involuntary movements, cognitive decline, and behavioral changes. Pathologically, patients with HD show selective striatal neuronal vulnerability at the early disease stage, although the mutant protein is ubiquitously expressed. Activation of the immune system and glial cell-mediated neuroinflammatory responses are early pathological features and have been found in all neurodegenerative diseases (NDDs), including HD. However, the role of inflammation in HD, as well as its therapeutic significance, has been less extensively studied compared to other NDDs. This review highlights the significantly elevated levels of inflammatory proteins and cellular markers observed in various HD animal models and HD patient tissues, emphasizing the critical roles of microglia, astrocytes, and oligodendrocytes in mediating neuroinflammation in HD. Moreover, it expands on recent discoveries related to the peripheral immune system's involvement in HD. Although current immunomodulatory treatments and inflammatory biomarkers for adjunctive diagnosis in HD are limited, targeting inflammation in combination with other therapies, along with comprehensive personalized treatment approaches, shows promising therapeutic potential. [ABSTRACT FROM AUTHOR]

Reversible data-hiding in encrypted images (RDHEI) plays a pivotal role in preserving privacy within images stored on cloud platforms. Recently, Wang et al. introduced a dual-stage permutation encryption scheme, which is highly compatible with RDHEI techniques. In this study, we undertake an exhaustive examination of the characteristics inherent to the dual-stage permutation scheme and propose two cryptanalysis schemes leveraging a large-kernel convolutional neural network (LKCNN) and a known plaintext attack (KPA) scheme, respectively. Our experimental findings demonstrate the effectiveness of our cryptanalysis schemes in breaking the dual-stage permutation encryption scheme. Based on our investigation, we highlight significant security vulnerabilities in the dual-stage permutation encryption scheme, raising concerns about its suitability for secure image storage and privacy protection in cloud environments. [ABSTRACT FROM AUTHOR]

Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms, which increase the chance of infection relapses. Here, we screened a small-molecule New Prestwick Chemical Library, consisting of 1,200 FDA-approved off-patent drugs against C. albicans, C. auris, and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens and their ability to kill preformed biofilms. Our studies identified the bis-biguanide alexidine dihydrochloride (AXD) as a drug with the highest antifungal and antibiofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mouse central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.IMPORTANCE The prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multidrug-resistant strains such as C. auris High mortality related to fungal infections points to major limitations of current antifungal therapy and an unmet need for new antifungal drugs. We screened a library of repurposed FDA-approved inhibitors to identify compounds with activities against a diverse range of fungi in varied phases of growth. The assays identified alexidine dihydrochloride (AXD) to have pronounced antifungal activity, including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro and prevented biofilm growth in vivo Thus, AXD has the potential to be developed as a pan-antifungal, antibiofilm drug.

Previous studies have shown that intravenous normal saline (NS) may be associated with the incidence of acute kidney injury (AKI). This study aimed to evaluate the association between the volume of NS infusion and AKI in heat stroke (HS) patients. This multicenter retrospective cohort study included 138 patients with HS. The primary outcome was the incidence of AKI. Secondary outcomes included the need for continuous renal replacement therapy (CRRT), admission to the intensive care unit (ICU), length of stay in the ICU and hospital, and in-hospital mortality. Multivariate regression models, random forest imputation, and genetic and propensity score matching were used to explore the relationship between NS infusion and outcomes. The mean volume of NS infusion in the emergency department (ED) was 3.02 ± 1.45 L. During hospitalization, 33 patients (23.91%) suffered from AKI. In the multivariate model, as a continuous variable (per 1 L), the volume of NS infusion was associated with the incidence of AKI (OR, 2.51; 95% CI, 1.43–4.40; p =.001), admission to the ICU (OR, 3.46; 95% CI 1.58–7.54; p =.002), and length of stay in the ICU (β, 1.00 days; 95% CI, 0.44–1.56; p <.001) and hospital (β, 1.41 days; 95% CI, 0.37–2.45; p =.008). These relationships also existed in the forest imputation cohort and matching cohort. There were no differences in the use of CRRT or in-hospital mortality. The volume of NS infusion was associated with a significant increase in the incidence of AKI, admission to the ICU, and length of stay in the ICU and hospital among patients with HS. [ABSTRACT FROM AUTHOR]

Data hiding in digital images is a potent solution for covert communication, embedding sensitive data into cover images. However, most existing methods are tailored for one-to-one scenarios, which present security risks. To mitigate this vulnerability, we introduce an innovative one-to-two data hiding scheme that employs a two-tier bit-flipping strategy to embed sensitive data in dual images. This process produces two stego images which are then transmitted to two distinct recipients who cannot extract any sensitive data alone. The sensitive data can only be extracted when the two recipients trust each other. Through this method, we can secure the stego images. The experimental results illustrate that our method achieves an excellent data payload while maintaining high visual quality. [ABSTRACT FROM AUTHOR]