Exploring the destructive synergy between IL-33 and Suilysin hemolysis on blood-brain barrier stability.

Streptococcus suis type 2 (SS2) is a zoonotic pathogen capable of eliciting meningitis, presenting significant challenges to both the swine industry and public health. Suilysin (Sly), one of SS2 most potent virulence determinants, releases a surfeit of inflammatory agents following red blood cell lysis. Notably, while current research on Sly role in SS2-induced meningitis predominantly centers on its interaction with the blood-brain barrier (BBB), the repercussions of Sly hemolytic products on BBB function have largely been sidestepped. In this vein, our study delves into the ramifications of Sly-induced hemolysis on BBB integrity. We discern that Sly hemolytic derivatives exacerbate the permeability of Sly-induced in vitro BBB models. Within these Sly hemolytic products, Interleukin-33 (IL-33) disrupts the expression and distribution of Claudin-5 in brain microvascular endothelial cells, facilitating the release of Interleukin-6 (IL-6) and Interleukin-8 (IL-8), thereby amplifying BBB permeability. Preliminary mechanistic insights suggest that IL-33-driven expression of IL-6 and IL-8 is orchestrated by the p38-mitogen-activated protein kinase signaling, whereas matrix metalloproteinase 9 mediates IL-33-induced suppression of Claudin-5. To validate these in vitro findings, an SS2-infected mouse model was established, and upon intravenous administration of growth stimulation expressed gene 2 (ST2) antibodies, in vivo results further underscored the pivotal role of the IL-33/ST2 axis during SS2 cerebral invasion. In summation, this study pioneerly illuminates the involvement of Sly hemolytic products in SS2-mediated BBB compromise and spotlights the instrumental role and primary mechanism of IL-33 therein. These insights enrich our comprehension of SS2 meningitis pathogenesis, laying pivotal groundwork for therapeutic advancements against SS2-induced meningitis.IMPORTANCEThe treatment of meningitis caused by Streptococcus suis type 2 (SS2) has always been a clinical challenge. Elucidating the molecular mechanisms by which SS2 breaches the blood-brain barrier (BBB) is crucial for the development of meningitis therapeutics. Suilysin (Sly) is one of the most important virulence factors of SS2, which can quickly lyse red blood cells and release large amounts of damage-associated molecular patterns, such as hemoglobin, IL-33, cyclophilin A, and so on. However, the impact of these hemolytic products on the function of BBB is unknown and ignored. This study is the first to investigate the effect of Sly hemolytic products on BBB function. The data are crucial for the study of the pathogenesis of SS2 meningitis and can provide an important reference for the development of meningitis therapeutics.

Acinetobacter nosocomialis utilizes a unique type VI secretion system to promote its survival in niches with prey bacteria.

Pathogenic bacteria of the Acinetobacter genus pose a severe threat to human health worldwide due to their strong adaptability, tolerance, and antibiotic resistance. Most isolates of these bacteria harbor a type VI secretion system (T6SS) that allows them to outcompete co-residing microorganisms, but whether this system is involved in acquiring nutrients from preys remains less studied. In this study, we found that Ab25, a clinical isolate of Acinetobacter nosocomialis, utilizes a T6SS to kill taxonomically diverse microorganisms, including bacteria and fungi. The T6SS of Ab25 is constitutively expressed, and among the three predicted effectors, T6e1, a member of the RHS effector family, contributes the most for its antimicrobial activity. T6e1 undergoes self-cleavage, and a short carboxyl fragment with nuclease activity is sufficient to kill target cells via T6SS injection. Interestingly, strain Ab25 encodes an orphan VgrG protein, which when overexpressed blocks the firing of its T6SS. In niches such as dry plastic surfaces, the T6SS promotes prey microorganism-dependent survival of Ab25. These results reveal that A. nosocomialis employs T6SSs that are highly diverse in their regulation and effector composition to gain a competitive advantage in environments with scarce nutrient supply and competing microbes.IMPORTANCEThe type VI secretion system (T6SS) plays an important role in bacterial adaptation to environmental challenges. Members of the Acinetobacter genus, particularly A. baumannii and A. nosocomialis, are notorious for their multidrug resistance and their ability to survive in harsh environments. In contrast to A. baumannii, whose T6SS has been well-studied, few research works have focused on A. nosocomialis. In this study, we found that an A. nosocomialis strain utilizes a contitutively active T6SS to kill diverse microorganisms, including bacteria and fungi. Although T6SS structural proteins of A. nosocomialis are similar to those of A. baumannii, the effector repertoire differs greatly. Interestingly, the T6SS of the A. nosocomialis strain codes for an ophan VgrG protein, which blocks the firing of the system when overexpressed, suggesting the existence of a new regulatory mechanism for the T6SS. Importantly, although the T6SS does not provide an advantage when the bacterium is grown in nutrient-rich medium, it allows A. nosocomialis to survive better in dry surfaces that contain co-existing bacteria. Our results suggest that killing of co-residing microorganisms may increase the effectiveness of strategies designed to reduce the fitness of Acinetobacter bacteria by targeting their T6SS.

A novel improved total variation algorithm for the elimination of scratch-type defects in high-voltage cable cross-sections.

In the quality inspection process of high-voltage cables, several commonly used indicators include cable length, insulation thickness, and the number of conductors within the core. Among these factors, the count of conductors holds particular significance as a key determinant of cable quality. Machine vision technology has found extensive application in automatically detecting the number of conductors in cross-sectional images of high-voltage cables. However, the presence of scratch-type defects in cut high-voltage cable cross-sections can significantly compromise the precision of conductor count detection. To address this problem, this paper introduces a novel improved total variation (TV) algorithm, marking the first-ever application of the TV algorithm in this domain. Considering the staircase effect, the direct use of the TV algorithm is prone to cause serious loss of image edge information. The proposed algorithm firstly introduces multimodal features to effectively mitigate the staircase effect. While eliminating scratch-type defects, the algorithm endeavors to preserve the original image's edge information, consequently yielding a noteworthy enhancement in detection accuracy. Furthermore, a dataset was curated, comprising images of cross-sections of high-voltage cables of varying sizes, each displaying an assortment of scratch-type defects. Experimental findings conclusively demonstrate the algorithm's exceptional efficiency in eradicating diverse scratch-type defects within high-voltage cable cross-sections. The average scratch elimination rate surpasses 90%, with an impressive 96.15% achieved on cable sample 4. A series of conducted ablation experiments in this paper substantiate a significant enhancement in cable image quality. Notably, the Edge Preservation Index (EPI) exhibits an improvement of approximately 20%, resulting in a substantial boost to conductor count detection accuracy, thus effectively enhancing the quality of high-voltage cable production.

Exercise Reverses Immune-Related Genes in the Hippocampus of Multiple Sclerosis Patients.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelinating lesions in the white matter of the central nervous system. Studies have shown that exercise is beneficial for multiple sclerosis (MS). However, the molecular basis is largely unknown. MATERIALS AND METHODS: We integrated multiple blood and hippocampus transcriptome data from subjects with physical activity or MS. Transcription change associations between physical activity and MS were analyzed with bioinformatic methods including GSEA (Gene Set Enrichment Analysis) and GO (Gene Ontology) analysis. RESULTS: We find that exercise can specifically reverse immune-related genes in the hippocampus of MS patients, while this effect is not observable in blood. Moreover, many of these reversed genes encode immune-related receptors. Interestingly, higher levels of physical activity have more pronounced effects on the reversal of MS-related transcripts. CONCLUSIONS: The immune-response related genes or pathways in the hippocampus may be the targets of exercise in alleviating MS conditions, which may offer new therapeutic clues for MS.

Immune-cell-mediated tissue engineering strategies for peripheral nerve injury and regeneration.

During the process of peripheral nerve repair, there are many complex pathological and physiological changes, including multi-cellular responses and various signaling molecules, and all these events establish a dynamic microenvironment for axon repair, regeneration, and target tissue/organ reinnervation. The immune system plays an indispensable role in the process of nerve repair and function recovery. An effective immune response not only involves innate-immune and adaptive-immune cells but also consists of chemokines and cytokines released by these immune cells. The elucidation of the orchestrated interplay of immune cells with nerve regeneration and functional restoration is meaningful for the exploration of therapeutic strategies. This review mainly enumerates the general immune cell response to peripheral nerve injury and focuses on their contributions to functional recovery. The tissue engineering-mediated strategies to regulate macrophages and T cells through physical and biochemical factors combined with scaffolds are discussed. The dynamic immune responses during peripheral nerve repair and immune-cell-mediated tissue engineering methods are presented, which provide a new insight and inspiration for immunomodulatory therapies in peripheral nerve regeneration.

Correlation between Combined Urinary Metal Exposure and Grip Strength under Three Statistical Models: A Cross-sectional Study in Rural Guangxi.

Objective: This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods: We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength. Results: In the multimetal linear regression, Cu (ß = -2.119), As (ß = -1.318), Sr (ß = -2.480), Ba (ß = 0.781), Fe (ß = 1.130) and Mn (ß = -0.404) were significantly correlated with grip strength ( P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95% confidence interval: -1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn ( P interactions of 0.003 and 0.018, respectively). Conclusion: In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Activation of PI3K/Akt pathway by G protein-coupled receptor 37 promotes resistance to cisplatin-induced apoptosis in non-small cell lung cancer.

OBJECTIVES: Lung cancer is a major public health concern and represents the most common cause of cancer-related death worldwide. Among eukaryotes, the G protein-coupled receptor (GPCR) family stands as the largest group of membrane proteins. Alterations in GPCR gene expression and dysregulation of signal transduction have been recognized as the markers of malignancy. As a member of the GPCR family, G protein-coupled receptor 37 (GPR37) exhibits unknown functions in tumors, particularly in non-small-cell lung cancer (NSCLC) METHODS: We explored the expression and prognosis of GPR37 in NSCLC through TCGA, GTEx, GEO, and GEPIA2. We detected the expression of GPR37 in NSCLC tissues and cell lines. The study explored the influence of GPR37 on tumor cell proliferation. Furthermore, we examined the effects of GPR37 on tumor cell apoptosis and invasion. Most importantly, we investigated whether GPR37 affects cisplatin-induced drug resistance in NSCLC. Furthermore, by conducting animal experiments, we assessed the impact of GPR37 on NSCLC and delved into underlying mechanisms. RESULTS: (1) In NSCLC, the expression of GPR37 is markedly higher than that in corresponding normal tissues. We found that elevated GPR37 expression predicts an unfavorable prognosis. (2) It was demonstrated that GPR37 positively regulates NSCLC cell invasion, migration, and proliferation, suppresses cell apoptosis, heightens resistance to cisplatin, and promotes tumor formation and growth. Conversely, we observed that GPR37 knockdown suppresses NSCLC cell invasion, migration, and proliferation, promotes cell apoptosis, increases sensitivity to cisplatin, and affects tumor formation and growth. (3) GPR37 activates PI3K/Akt/mTOR signal transduction pathways to mediate epithelial-mesenchymal transition (EMT), thereby promoting the progression of NSCLC. CONCLUSIONS: It was suggested that GPR37 acts a crucial role in promoting the occurrence and development of NSCLC. Knockdown of GPR37 significantly inhibits the occurrence and development of NSCLC. Therefore, our findings demonstrated that GPR37 may represent a viable therapeutic target for NSCLC.

Bionic peptide scaffold in situ polarization and recruitment of M2 macrophages to promote peripheral nerve regeneration.

Tissue regeneration requires exogenous and endogenous signals, and there is increasing evidence that the exogenous microenvironment may play an even more dominant role in the complex process of coordinated multiple cells. The short-distance peripheral nerve showed a spontaneous regenerative phenomenon, which was initiated by the guiding role of macrophages. However, it cannot sufficiently restore long-distance nerve injury by itself. Based on this principle, we firstly constructed a proinflammatory model to prove that abnormal M2 expression reduce the guidance and repair effect of long-distance nerves. Furthermore, a bionic peptide hydrogel scaffold based on self-assembly was developed to envelop M2-derived regenerative cytokines and extracellular vesicles (EVs). The cytokines and EVs were quantified to mimic the guidance and regenerative microenvironment in a direct and mild manner. The bionic scaffold promoted M2 transformation in situ and led to proliferation and migration of Schwann cells, neuron growth and motor function recovery. Meanwhile, the peptide scaffold combined with CX3CL1 recruited more blood-derived M2 macrophages to promote long-distance nerve reconstruction. Overall, we systematically confirmed the important role of M2 in regulating and restoring the injury peripheral nerve. This bionic peptide hydrogel scaffold mimicked and remodeled the local environment for M2 transformation and recruitment, favoring long-distance peripheral nerve regeneration. It can help to explicate regulative effect of M2 may be a cause not just a consequence in nerve repair and tissue integration, which facilitating the development of pro-regenerative biomaterials.

Non-human primate models and systems for gait and neurophysiological analysis.

Brain-computer interfaces (BCIs) have garnered extensive interest and become a groundbreaking technology to restore movement, tactile sense, and communication in patients. Prior to their use in human subjects, clinical BCIs require rigorous validation and verification (V&V). Non-human primates (NHPs) are often considered the ultimate and widely used animal model for neuroscience studies, including BCIs V&V, due to their proximity to humans. This literature review summarizes 94 NHP gait analysis studies until 1 June, 2022, including seven BCI-oriented studies. Due to technological limitations, most of these studies used wired neural recordings to access electrophysiological data. However, wireless neural recording systems for NHPs enabled neuroscience research in humans, and many on NHP locomotion, while posing numerous technical challenges, such as signal quality, data throughout, working distance, size, and power constraint, that have yet to be overcome. Besides neurological data, motion capture (MoCap) systems are usually required in BCI and gait studies to capture locomotion kinematics. However, current studies have exclusively relied on image processing-based MoCap systems, which have insufficient accuracy (error: ≥4° and 9 mm). While the role of the motor cortex during locomotion is still unclear and worth further exploration, future BCI and gait studies require simultaneous, high-speed, accurate neurophysiological, and movement measures. Therefore, the infrared MoCap system which has high accuracy and speed, together with a high spatiotemporal resolution neural recording system, may expand the scope and improve the quality of the motor and neurophysiological analysis in NHPs.

Immune checkpoint inhibitors related respiratory disorders in patients with lung cancer: A meta-analysis of randomized controlled trials.

Background: In recent years, immune checkpoint inhibitors (ICIs) had extremely rapid growth in anti-cancer and improved outcomes of many malignancies, specifically lung cancer. However, the incidence of ICIs-related adverse events also raised. Using this meta-analysis, ICIs-related respiratory disorders were investigated in lung cancer patients. Methods: Using Cochrane Library, Embase, and PubMed databases, we performed an integrated search for randomized controlled trials (RCTs) to compare respiratory disorders among different regimens. The data was prepared with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline, and the quality of included studies was evaluated based on the Cochrane manual. Results: In total, 22 RCTs were involved in this meta-analysis. Compared with ICIs, chemotherapy reduced the risk of interstitial lung disease (p = 0.03; SMD: 2.81; 95% CI: 1.08, 7.27), pleural effusion (p = 0.002; SMD: 2.12; 95% CI: 1.32, 3.42), and pneumonitis (p < 0.00001; SMD: 9.23; 95% CI: 4.57, 18.64). ICIs plus chemotherapy could provide a higher probability for patients to suffer pneumonitis than chemotherapy (p = 0.01; SMD: 1.96; 95% CI: 1.17, 3.28). In addition, single ICI brought a lower likelihood for patients suffering pneumonitis than double ICIs (p = 0.004; SMD: 2.17; 95% CI: 1.27, 3.69). Conclusion: ICIs-based treatment, such as ICIs alone, ICIs plus chemotherapy and double ICIs, can raise the incidences of some respiratory disorders in patients with lung cancer. It suggests that ICIs should be conducted based on a comprehensive consideration to prevent ICIs-related respiratory disorders. To a certain degree, this study might be provided to the clinician as a reference for ICIs practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022378901, identifier (CRD42022378901).

Acinetobacter baumannii Kills Fungi via a Type VI DNase Effector.

Many Gram-negative bacteria deploy a type VI secretion system (T6SS) to inject toxins into target cells to promote their survival and replication in complex environments. Here, we report that Acinetobacter baumannii uses its T6SS to kill fungi and that the effector TafE (ACX60_15365) is responsible for such killing. Although ectopically expressed TafE is toxic to both Escherichia coli and Saccharomyces cerevisiae, deletion of tafE only affects the antifungal activity of A. baumannii. We demonstrate that TafE is a DNase capable of targeting the nuclei of yeast cells and that an Ntox15 domain is essential for its ability to degrade DNA. Furthermore, our findings show that A. baumannii is protected from the toxicity of TafE by elaborating the immunity protein TaeI (ACX60_15360), which antagonizes the activity of the effector by direct binding. The discovery of A. baumannii T6SS effectors capable of killing multiple taxonomically distinct microbes has shed light on a mechanism of the high-level fitness of this pathogen in environments characterized by scarce nutrients and the potential presence of diverse microorganisms. IMPORTANCE Acinetobacter baumannii is an increasing important nosocomial pathogen that is difficult to combat due to its ability to survive in harsh environments and the emergence of isolates that are resistant to multiple antibiotics. A better understanding of the mechanism underlying the toughness of A. baumannii may identify its Achilles' heel, which will facilitate the development of novel preventive and treatment measures. In this study, our findings show that A. baumannii kills fungi with the DNase effector TafE injected into competitor cells by its type VI secretion system. A. baumannii is protected from the activity of TafE by the immunity protein TaeI, which inactivates the effector by direct binding. Our results suggest that inactivation of its T6SS or effectors may reduce the fitness of A. baumannii and increase the effectiveness of treatment by means such as antibiotics. Furthermore, our finding suggests that targeted degradation of TaeI may be an effective strategy to kill A. baumannii.

Effects of the retrieval-extinction paradigm with abstract reminders on fear memory extinction.

Reactivated fear memories may enter an unstable state that could be interrupted by behavioral interventions such as the retrieval-extinction procedure. Studies of pharmacological interventions have shown that retrieval cues are not necessarily an exact reduplication of initial conditioned stimuli (CSs); they can instead be abstract word cues. However, the effectiveness of using abstract reminder cues in behavioral intervention procedures remains unknown, as do the conditions under which they are effective. The typicality of CS and the abstraction level of reminders are also likely to be important in the paradigm but have not been investigated to date. Here, in three experiments (n = 107), we manipulate the fear conditioning process, including single CS-unconditioned stimulus (US) and multiple CS-US connections, as well as the CS typicality and abstraction level of reminder cues, to explore the conditions for adopting retrieval-extinction with abstract reminders. The results of Experiments 1 and 2 show that the abstract cue is ineffective for use as a reminder in the procedure; this is the case for single exemplar category learning and perceptual discriminative learning, independent of the typicality of CS+ or the abstraction level of reminder cues. Only the outcome of Experiment 3, which contains multiple CS-US connections, shows no indication of fear return. The limitations of the study and possible interpretations of the results are discussed.

Development and Validation of the Counter-Empathy Scale.

Counter-empathy refers to an emotional response that is valence-opposite from the emotional state of another individual. Screening for counter-empathy characteristics is of great significance for social psychology, clinical psychology, and criminal psychology research. Unfortunately, until now, there has been no specific scale to measure counter-empathy, creating a main bottleneck in counter-empathy research. We developed and validated a new instrument to measure counter-empathy: the Counter-Empathy Scale (CES). We tested the CES in a survey of 1265 Chinese college students. Both exploratory factor analysis and confirmatory factor analysis revealed a clear two-factor structure (feeling annoyed with others' happiness and taking pleasure in others' pain) for the CES. The CES is internally consistent, test-retest stable, and acceptable in terms of criterion-related validity. In conclusion, the CES is a promising instrument to assess counter-empathy.

Anwuligan inhibits the progression of non-small cell lung cancer via let-7c-3p/PI3K/AKT/mTOR axis.

BACKGROUND: Anwuligan (ANW) isolated from nutmeg, also known as myristyl lignan, has attracted attention due to its therapeutic potential in diseases. However, its effect on lung cancer is still unclear. METHODS: In this study, the cytotoxicity of ANW on non-small cell lung cancer (NSCLC) cells was detected using a Cell Counting Kit-8 (CCK-8) assay. In vitro, clone formation, wound healing, and Transwell assays were used to investigate the migratory and invasive abilities of NSCLC cells after ANW treatment. The expression levels of the associated proteins were detected using Western blotting. A luciferase assay was used to validate the binding of let-7c-3p to the 3'-untranslated region (UTR) of PIK3CA. In vivo, an A549 cell xenograft mouse model was used to verify the effect of ANW on tumor growth. RESULTS: The results showed that ANW treatment (20 or 50 µM) had obvious cytotoxicity against A549 and H460 cells, suppressing cell proliferation and migration in vitro. In vivo, the growth of the implanted tumor was inhibited by ANW in a nude mouse model. The growth of NSCLC cells was also inhibited by let-7c-3p overexpression in vitro and in vivo. The inhibitory effect of ANW on the proliferation and metastasis of NSCLC cells was weakened by the downregulation of let-7c-3p, whereas it was enhanced by the overexpression of let-7c-3p; PIK3CA was the main target of let-7c-3p. CONCLUSIONS: In summary, ANW inhibits the growth and metastasis of NSCLC cells in vivo and in vitro by upregulating the expression of let-7c-3p, which can regulate the PI3K/AKT/mTOR signaling pathway. PIK3CA is the main target of let-7c-3p.

Cannabidiol inhibits invasion and metastasis in colorectal cancer cells by reversing epithelial-mesenchymal transition through the Wnt/ß-catenin signaling pathway.

Colorectal cancer (CRC) is the leading cause of cancer deaths worldwide, wherein distant metastasis is the main reason for death. The non-psychoactive phytocannabinoid cannabidiol (CBD) effectively induces the apoptosis of CRC cells. We investigated the role of CBD in the migration and metastasis of CRC cells. CBD significantly inhibited proliferation, migration, and invasion of colon cancer cells in a dose- or time-dependent manner. CBD could also inhibit epithelial-mesenchymal transition (EMT) by upregulating epithelial markers such as E-cadherin and downregulating mesenchymal markers such as N-cadherin, Snail, Vimentin, and HIF-1α. CBD could suppress the activation of the Wnt/ß-catenin signaling pathway, inhibit the expression of ß-catenin target genes such as APC and CK1, and increase the expression of Axin1. Compared to the control group, the volume and weight of orthotopic xenograft tumors significantly decreased after the CBD treatment. The results demonstrated that CBD inhibits invasion and metastasis in CRC cells. This was the first study elucidating the underlying molecular mechanism of CBD in inhibiting EMT and metastasis via the Wnt/ß-catenin signaling pathway in CRC cells. The molecular mechanism by which CBD inhibits EMT and metastasis of CRC cells was shown to be through the Wnt/ß-catenin signaling pathway for the first time.

Stimulus diversity increases category-based fear generalization and the effect of intolerance of uncertainty.

Fear generalization refers to conditioned fear responses extending to related stimuli and fear overgeneralization is a key feature of pathological anxiety. Along with perception similarity, conceptual relations affect fear generalization. We investigated whether stimulus diversity-an important principle of category-based induction-influences fear generalization. Induction studies have shown that generalization from a premise involving diverse instances is stronger than that from non-diverse instances. We adopted this framework for fear learning and established two groups. The diverse group developed fear in response to diverse instances from one category, while the non-diverse group acquired fear of non-diverse instances from the same category. An effect of stimulus diversity was observed in shock-expectancy ratings, with the diverse group displaying higher fear generalization than the non-diverse group. We also tested whether intolerance of uncertainty (IU) might affect the difference in fear generalization between the two conditions. Individuals with higher IU showed reduced difference in fear generalization between two conditions, mainly driven by heightened fear generalization to novel stimulus with ambiguous threat levels in the non-diverse condition. This study helps illustrate the mechanisms behind differential category-based fear generalization and provides a potential explanation for why higher IU individuals may develop anxiety disorders following trauma.

A Trojan horse biomimetic delivery system using mesenchymal stem cells for HIF-1α siRNA-loaded nanoparticles on retinal pigment epithelial cells under hypoxia environment.

AIM: To demonstrate the feasibility of mesenchymal stem cell (MSC)-mediated nano drug delivery, which was characterized by the "Trojan horse"-like transport of hypoxia-inducible factor-1α small interfering RNA (HIF-1α siRNA) between MSCs and retinal pigment epithelial cells (RPE) under hypoxia environment. METHODS: Plasmid and lentivirus targeting the human HIF-1α gene were designed and constructed. HIF-1α siRNA was encapsulated into poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) through the water-in-oil-in-water (w/o/w) multiple emulsion technique. The effect of PLGA-NPs uptake on the expression of HIF-1α mRNA was tested in RPE cells by real-time quantitative polymerase chain reaction (qPCR) and additional transfected conditions were used as control, including lentivirus group, nude plasmid group and blank PLGA group. MSCs were transfected with the NPs and the transfection efficacy was evaluated by flow cytometry. Transwell co-culture system of transfected MSCs and RPE cells was constructed under hypoxia environment. The effects of MSC-loaded HIF-1α siRNA PLGA-NPs on proliferation, apoptosis, and migration of RPE cells were then evaluated. The effect of transfected MSCs on HIF-1α expression of RPE cells was analyzed by using qPCR at the time points 24h, 3d, and 7d. RESULTS: The average diameter of PLGA-NPs loaded with HIF siRNA was 314.1 nm and the zeta potential was -0.36 mV. The transfection efficiency of PLGA-NPs was 67.3%±5.2% into MSCs by using flow cytometry. Compared with the lentivirus group, the PLGA-NPs loaded with HIF-1α siRNA can effectively reduce the expression of HIF-1α mRNA up to 7d in RPE (0.63±0.05 at 7d, P<0.001). In the Transwell co-culture system of transfected MSCs and RPE, the abilities of proliferation (2.34±0.17, 2.40±0.28, 2.47±0.24 at 48h, F=0.23, P=0.80), apoptosis (14.83%±2.43%, 12.94%±2.19%, 12.39%±3.21%; F=0.70, P=0.53) and migration (124.5±7.78, 119.5±5.32, 130±9.89, F=1.33, P=0.33) of the RPE cells had no differences between MSC-loaded HIF-1α siRNA PLGA-NPs and other groups. The inhibition of PLGA on the HIF-1α mRNA expression in RPE cells could continue until the 7th day, the level of HIF-1α mRNA was lower than that of other groups (F=171.98, P<0.001). CONCLUSION: The delivery of PLGA-NPs loaded with HIF-1α siRNA carried by MSCs is found to be beneficial temporally for HIF-1α mRNA inhibition in RPE cells under hypoxia environment. The MSC-based bio-mimetic delivery of HIF-1α siRNA nanoparticles is a potential method for therapy against choroidal neovascularization.

Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1-2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL.Trial registration: chictr.org.cn number, ChiCTR1900023309.

A natural compound hyperoside targets Salmonella Typhimurium T3SS needle protein InvG.

The antimicrobial actions of natural compounds derived from medicinal plants have been well documented. However, their detailed mechanisms underlying the action against microorganisms remain largely unexplored. Salmonella enterica is a common pathogen causing both gastrointestinal and systemic diseases. In Salmonella enterica, the type III secretion system (T3SS) is employed to export secreted effectors directly to the cytoplasm of host cells. Using a SipA-ß-lactamase reporter, we found that hyperoside (HYP) inhibited the activity of Salmonella T3SS needle protein InvG, prevented damage to host cells and protected mice against Salmonella enterica serovar Typhimurium. It was also observed that HYP binds to InvG directly through hydrogen-bridged cations and hydrophobic interactions. The unique mechanism of antibacterial action of HYP suggested that it could be used as a potentially effective candidate for future antimicrobial regimens.

MF59 Promoted the Combination of CpG ODN1826 and MUC1-MBP Vaccine-Induced Antitumor Activity Involved in the Enhancement of DC Maturation by Prolonging the Local Retention Time of Antigen and Down-Regulating of IL-6/STAT3.

Our previous study found that CpG oligodeoxynucleotides 1826 (CpG 1826), combined with mucin 1 (MUC1)-maltose-binding protein (MBP) (M-M), had certain antitumor activity. However, this combination is less than ideal for tumor suppression (tumors vary in size and vary widely among individuals), with a drawback being that CpG 1826 is unstable. To solve these problems, here, we evaluate MF59/CpG 1826 as a compound adjuvant with M-M vaccine on immune response, tumor suppression and survival. The results showed that MF59 could promote the CpG 1826/M-M vaccine-induced tumor growth inhibition and a Th1-prone cellular immune response, as well as reduce the individual differences of tumor growth and prolonged prophylactic and therapeutic mouse survival. Further research showed that MF59 promotes the maturation of DCs stimulated by CpG1826/M-M, resulting in Th1 polarization. The possible mechanism is speculated to be that MF59 could significantly prolong the retention time of CpG 1826, or the combination of CpG 1826 and M-M, as well as downregulate IL-6/STAT3 involved in MF59 combined CpG 1826-induced dendritic cell maturation. This study clarifies the utility of MF59/CpG 1826 as a vaccine compound adjuvant, laying the theoretical basis for the development of a novel M-M vaccine.