Low-dose IL-2 Treatment Rescues Cognitive Deficits by Repairing the Imbalance Between Treg and Th17 Cells at the Middle Alzheimer's Disease Stage.

Multiple studies highlight the role of effector and regulatory CD4+T cells in the pathophysiology of Alzheimer's disease, and foster low-dose IL-2 treatment which induces regulatory CD4+T (Treg) cells expansion and activation as a promising strategy for its treatment. However, studies demonstrating discrepant Treg functions in AD have been reported. In addition, a compromised immune system associated with aging may substantially impact on these processes. Here, we report that there is an altered balance of activity between Treg cells and IL-17-producing helper T (Th17) cells in periphery and brain of APP/PS1 mice along the disease progression. A dramatic loss of the healthy balance of activity between Treg and Th17 cells was found at the middle disease stage. While peripheral low-dose recombinant human IL-2 administration could selectively modulate the abundance of Treg cells and repair the imbalance between Treg and Th17 subsets at the middle disease stage. We further show that modulation of peripheral immune balance through low-dose IL-2 treatment reduces the neuro-inflammation and increases numbers of plaque-associated microglia, accompanied by marked reduction of Aß plaque deposition and slower cognitive declines in APP/PS1 mice at the middle disease stage. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of the homeostasis of CD4+T cell subsets in Alzheimer's disease at the middle disease stage.

Autoimmune uveitis in Behçet's disease and Vogt-Koyanagi-Harada disease differ in tissue immune infiltration and T cell clonality.

Objectives: Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet's disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD can show similar clinical manifestations, but the underlying immunopathogenesis remains unclear. Methods: To understand immune landscapes in inflammatory eye tissues, we performed single-cell RNA paired with T cell receptor (TCR) sequencing of immune cell infiltrates in aqueous humour from six patients with BD (N = 3) and VKHD (N = 3) uveitis patients. Results: Although T cells strongly infiltrated in both types of autoimmune uveitis, myeloid cells only significantly presented in BD uveitis but not in VKHD uveitis. Conversely, VKHD uveitis but not BD uveitis showed an overwhelming dominance by CD4+ T cells (> 80%) within the T cell population due to expansion of CD4+ T cell clusters with effector memory (Tem) phenotypes. Correspondingly, VKHD uveitis demonstrated a selective expansion of CD4+ T cell clones which were enriched in pro-inflammatory Granzyme H+ CD4+ Tem cluster and showed TCR and Th1 pathway activation. In contrast, BD uveitis showed a preferential expansion of CD8+ T cell clones in pro-inflammatory Granzyme H+ CD8+ Tem cluster, and pathway activation for cytoskeleton remodelling, cellular adhesion and cytotoxicity. Conclusion: Single-cell analyses of ocular tissues reveal distinct landscapes of immune cell infiltration and T-cell clonal expansions between VKHD and BD uveitis. Preferential involvements of pro-inflammatory CD4+ Th1 cells in VKHD and cytotoxic CD8+ T cells in BD suggest a difference in disease immunopathogenesis and can guide precision disease management.

T follicular helper 17 (Tfh17) cells are superior for immunological memory maintenance.

A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2, and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17, respectively. Here, we developed a new method to induce Tfh1, Tfh2, and Tfh17-like (iTfh1, iTfh2, and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.

Indole acetylated high-amylose maize starch: Synthesis, characterization and application for amelioration of colitis.

Tryptophan metabolites such as indole-3-acetic acid (IAA) are critical for gut health, through their binding to the aryl hydrocarbon receptor (AhR), and may be useful for treatment of gastrointestinal diseases. Delivery of IAA to the colon is necessary, and one strategy is use of esterified starches which get digested in the colon by gut microbes. High amylose maize starch (HAMS) resists digestion in the upper gastrointestinal tract and is fermented by gut microbiota to release short-chain fatty acids (SCFAs), which are also beneficial to intestinal homeostasis. IAA esterified to HAMS (HAMSIAA) was synthesized with different degrees of substitution (DSs) by controlling the ratio of IAA vs HAMS. Successful incorporation of indole acetyl group was verified by NMR and FTIR spectra. XRD revealed that the crystalline type of HAMSIAA changed from B to V-type. SEM showed the destroyed surface of the starch granules. HAMSIAA with DS ~ 0.3 effectively increased IAA in the colon, to levels unachievable by oral IAA delivery. HAMSIAA increased pathways downstream of AhR activation, including CYP1A1 mRNA expression and IL-22 protein levels, and greatly improved DSS-induced colitis. HAMSIAA could serve as an ideal means for colon-targeted delivery of IAA and a promising nutraceutical for amelioration of inflammatory conditions.

Study on the Extrusion Molding Process of Polylactic Acid Micro Tubes for Biodegradable Vascular Stents.

Polylactic acid (PLA) has been widely used in the field of medical devices. However, few studies have been conducted on the extrusion molding of PLA micro tubes for the preparation of biodegradable vascular stents. In this paper, the extrusion die for PLA single-cavity micro tubes was designed and manufactured by micro-extrusion theory. Taking the outer diameter, wall thickness, wall thickness uniformity and ovality of micro tubes as the evaluation index, the influence of the main extrusion process parameters on the evaluation index was studied. The experimental results show that the outer diameter and wall thickness are significantly affected by screw speed, pulling speed and gas flow rate; extrusion process parameters have little influence on wall thickness uniformity and ovality within a certain range, which mainly depends on the processing accuracy and assembly accuracy of the extrusion die. However, excessively high screw speed and low gas flow rate have significant effects on ovality. Finally, according to the influence of extrusion process parameters on the evaluation index, a series of micro tubes that meet the design requirements are extruded and carved into vascular stent structures.

Digital Image Restoration Based on Multicontour Batch Scanning.

In order to explore the problem of digital image restoration, the authors propose a research on digital image restoration based on multicontour batch scanning. This method recommends key technical problems and solutions based on information represented by multicontour batch scans, exploring research in digital image restoration. Research has shown that the research on digital image restoration based on multicontour batch scanning is about 40% more efficient than traditional methods. Aiming at the new application of digital image inpainting, the application of image inpainting in image compression is studied in depth, and the technical principles of image inpainting and image compression are complemented.

Propionate Ameliorates Alcohol-Induced Liver Injury in Mice via the Gut-Liver Axis: Focus on the Improvement of Intestinal Permeability.

Alcohol-related liver disease (ALD) is a major cause of chronic liver disease worldwide with limited therapeutic options. Here, we first revealed the promising beneficial effect of gut microbiota-derived propionate on alcoholic liver injury in mice. This effect was dependent on the modulation of homeostasis of the gut-liver axis, especially the improvement of intestinal permeability. Dietary supplementation with propionate protected against ethanol-induced loss of hepatic function and hepatic steatosis in mice. Meanwhile, propionate treatment attenuated intestinal epithelial barrier dysfunction, restored the expression of intestinal mucus layer components, suppressed intestinal inflammation, and altered intestinal microbiota dysbiosis, which inhibited the intestinal hyperpermeability and subsequently reduced lipopolysaccharide leakage in ALD mice. Furthermore, as a consequence of endotoxemia amelioration, the liver inflammation-related TLR4-NF-κB pathway was inhibited. Collectively, our results suggested that propionate supplementation may be a promising option for the prevention and treatment of ALD.

Intelligent Recognition Algorithm-Based Color Doppler Ultrasound in the Treatment of Dangerous Placenta Previa.

The study focused on the clinical diagnostic value of color Doppler ultrasound of dangerous placenta previa patients under the guidance of intelligent recognition algorithms. 58 patients with placenta previa and placenta accreta admitted to the hospital for treatment were selected as research subjects. The color Doppler ultrasound under the guidance of intelligent recognition algorithm was compared with the two-dimensional ultrasound for specificity, sensitivity, and accuracy. The color Doppler ultrasound results showed that, of the 58 patients, there were 32 cases of complete placenta previa and 26 cases of incomplete placenta previa, which were consistent with the surgical pathology results. It was found that patients with malignant placenta previa and placenta accreta had thickened placenta, disappeared posterior placental space, myometrium <2 mm, and increased incidence of cervical enlargement (P < 0.05). In conclusion, the recognition accuracy of color Doppler ultrasound under the guidance of the intelligent recognition algorithm is more than 90%, and it can effectively identify dangerous placenta previa, assisting doctors in diagnosis and treatment of dangerous placenta previa.

Huangbai Liniment Ameliorates Skin Inflammation in Atopic Dermatitis.

Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD; however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3-4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1ß, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (TREG) cells and inhibiting the generation of TH1, TH2, and TH17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.

Selenium-GPX4 axis protects follicular helper T cells from ferroptosis.

Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of TFH cell survival remains unclear. Here we report that TFH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for TFH cell survival. The deletion of GPX4 in T cells selectively abrogated TFH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased TFH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.

Dimensionality reduction by UMAP reinforces sample heterogeneity analysis in bulk transcriptomic data.

Transcriptomic analysis plays a key role in biomedical research. Linear dimensionality reduction methods, especially principal-component analysis (PCA), are widely used in detecting sample-to-sample heterogeneity, while recently developed non-linear methods, such as t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP), can efficiently cluster heterogeneous samples in single-cell RNA sequencing analysis. Yet, the application of t-SNE and UMAP in bulk transcriptomic analysis and comparison with conventional methods have not been achieved. We compare four major dimensionality reduction methods (PCA, multidimensional scaling [MDS], t-SNE, and UMAP) in analyzing 71 large bulk transcriptomic datasets. UMAP is superior to PCA and MDS but shows some advantages over t-SNE in differentiating batch effects, identifying pre-defined biological groups, and revealing in-depth clusters in two-dimensional space. Importantly, UMAP generates sample clusters uncovering biological features and clinical meaning. We recommend deploying UMAP in visualizing and analyzing sizable bulk transcriptomic datasets to reinforce sample heterogeneity analysis.

Sustained low-dose interleukin-2 therapy alleviates pathogenic humoral immunity via elevating the Tfr/Tfh ratio in lupus.

OBJECTIVES: Low-dose interleukin-2 (IL-2) has shown promising clinical benefits in the treatment of systemic lupus erythematosus (SLE), but how this therapy alleviates pathogenic humoral immunity remains not well understood. The dilemma is that IL-2 can suppress both follicular helper and regulatory T (Tfh and Tfr) cells, which counteract each other in regulating autoantibody production. METHODS: Female NZB/W F1 mice received recombinant human IL-2 (3 × 104 IU/dose) in three treatment regimens: (1) short, daily for 7 days; (2) medium, daily for 14 days, and (3) long, every second day for 28 days. Tfh (Foxp3-CXCR5+Bcl6+), Tfr (Foxp3+CXCR5+Bcl6+), germinal centre (GC, B220+GL-7+Fas+) and antibody-secreting cell (ASC, B220-CD138+TACI+) were analysed by flow cytometry. Serum anti-dsDNA level was determined by ELISA. Kidney pathology was evaluated by H&E and immunofluorescence staining. Circulating Tfh and Tfr cells in SLE patients treated with low-dose IL-2 from a previous clinical trial (NCT02084238) was analysed. RESULTS: Low-dose IL-2 treatment consistently increased Tfr/Tfh ratio in mice and SLE patients, because of a stronger suppression on Tfh cells than Tfr cells. Three treatment regimens revealed distinct immunological features. Tfh suppression was observed in all regimens, but Tfr suppression and GC reduction were recorded in just medium and long regimens. Only the long treatment regimen resulted in inhibited ASC differentiation in spleen, which was accompanied by reduced anti-dsDNA titres and ameliorated kidney pathology. CONCLUSION: Low-dose IL-2 therapy increases the Tfr/Tfh ratio, and a less frequent and prolonged treatment can alleviate pathogenic humoral immunity and improve renal function.

The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses.

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.

Flow cytometric analysis of T lymphocytes and cytokines in aqueous humor of patients with varicella zoster virus-mediated acute retinal necrosis.

BACKGROUND: The purpose of this study is to investigate the aqueous humor (AH) T lymphocyte subsets and cytokines of acute retinal necrosis (ARN) to elucidate the immunologic inflammatory features of this disorder. METHODS: Three patients with ARN infected with varicella zoster virus (VZV) who underwent multiple intravitreal injections of ganciclovir were enrolled in this study. The control group consisted of four non-infectious patients with acute anterior uveitis (AAU). Flow cytometric analysis was performed on the lymphocyte subsets from the AH and peripheral blood (PB) samples during the active phase of intraocular inflammation. Five inflammatory cytokines were measured in each AH sample and various clinical characteristics were also assessed. RESULTS: VZV deoxyribonucleic acid (DNA) was detected by real-time polymerase chain reaction (PCR) in AH from all the ARN patients, who showed higher CD8+ T lymphocytes population in AH than the AAU patients (p = 0.006). CD4/CD8 ratios of T lymphocytes and the percentage of CD8 + CD25+ T lymphocytes in AH were significantly lower in ARN than in AAU (p = 0.006; p = 0.012). In the ARN patients, the percentages of CD4+ and CD8+ T lymphocytes in AH were higher than those found in PB. The percentage of CD4 + CD25+ T lymphocytes in AH was significantly higher than the proportion in PB in the AAU patients (p = 0.001). Immunoregulatory cytokine Interleukin-10 in AH was significantly elevated in the ARN patients in comparison with the case of the AAU patients (p = 0.036). In ARN, the copy number of VZV DNA in AH positively correlated with the percentage of CD8+ T lymphocytes in AH and negatively correlated with the CD4/CD8 ratio in AH during the course of disease treatment (p = 0.009, r = 0.92; p = 0.039, r = - 0.834). CONCLUSION: The ARN patients caused by VZV had different intraocular T lymphocyte subsets and cytokines profile than those of the non-infectious patients. High percentages of CD8+ T lymphocytes and low CD4/CD8 T cell ratios may be a potential biomarker for diagnosis of viral-infectious uveitis. T lymphocytes examination at the inflammatory sites has the potential to become a useful research tool for differentiating viral and non-viral uveitis.

High levels of soluble CD25 in COVID-19 severity suggest a divergence between anti-viral and pro-inflammatory T-cell responses.

OBJECTIVES: We aimed to gain an understanding of the paradox of the immunity in COVID-19 patients with T cells showing both functional defects and hyperactivation and enhanced proliferation. METHODS: A total of 280 hospitalised patients with COVID-19 were evaluated for cytokine profiles and clinical features including viral shedding. A mouse model of acute infection by lymphocytic choriomeningitis virus (LCMV) was applied to dissect the relationship between immunological, virological and pathological features. The results from the mouse model were validated by published data set of single-cell RNA sequencing (scRNA-seq) of immune cells in bronchoalveolar lavage fluid (BALF) of COVID-19 patients. RESULTS: The levels of soluble CD25 (sCD25), IL-6, IL-8, IL-10 and TNF-α were higher in severe COVID-19 patients than non-severe cases, but only sCD25 was identified as an independent risk factor for disease severity by multivariable binary logistic regression analysis and showed a positive association with the duration of viral shedding. In agreement with the clinical observation, LCMV-infected mice with high levels of sCD25 demonstrated insufficient anti-viral response and delayed viral clearance. The elevation of sCD25 in mice was mainly contributed by the expansion of CD25+CD8+ T cells that also expressed the highest level of PD-1 with pro-inflammatory potential. The counterpart human CD25+PD-1+ T cells were expanded in BALF of COVID-19 patients with severe disease compared to those with modest disease. CONCLUSION: These results suggest that high levels of sCD25 in COVID-19 patients probably result from insufficient anti-viral immunity and indicate an expansion of pro-inflammatory T cells that contribute to disease severity.

Reversible Information of Encrypted Image Based on Feature Difference Detection and Wavelet Transform.

Aiming at the shortcomings of the existing lossless digital watermarking algorithm based on frequency domain in reversibility and embedding capacity, this study proposes a lossless digital image watermarking algorithm based on fractional wavelet transform, which is used for large-capacity reversible information hiding of images. First, the image is transformed by LeGall5/3 fractional wavelet, and then, the watermark is embedded in the high-frequency subband by the histogram shift method. In order to obtain maximum embedding capacity and reduce image distortion, the methods of selecting embedding parameters and stopping parameters are proposed, respectively. At the same time, in order to prevent overflow and reduce additional information, a new method of generating position map is proposed. The experimental results show that Lena is the result of multilayer embedding based on the algorithm in this study. In order to better observe the distortion phenomenon and enlarge the image, the Lena test image is the watermark image obtained after two and three layers of embedding, and its embedding capacity can be 2.7 bpp. It is proved that wavelet transform is suitable for encrypted images to implement covert communication.

Chlorinated Flame-Retardant Dechlorane 602 Potentiates Type 2 Innate Lymphoid Cells and Exacerbates Airway Inflammation.

Chlorinated flame-retardant dechloranes are emerging substitutes for restricted flame retardants. Recent studies have demonstrated that they are accumulated in wildlife and detectable in humans; however, their effects on human health are poorly understood. Here, for the first time, we revealed that widely used chlorinated flame-retardant dechlorane 602 (Dec 602) exacerbated airway inflammation in two mouse models induced by house dust mite (HDM) or IL-33, respectively. Deteriorated airway inflammation by Dec 602 was associated with a higher production of type 2 cytokines including IL-4, IL-5, and IL-13, and IgE, accompanied by enhanced mRNA expression of proinflammatory cytokines such as TNF-α and IL-6. Mechanistically, we found that Dec 602 directly potentiated mouse and human group 2 innate lymphoid cells and, as such, promoted airway inflammation even in the absence of conventional T cells in Rag -/- mice. These findings provide novel immunological insights necessary for further studies of the health impact of emerging flame-retardant dechloranes including Dec 602.

Luteolin, an aryl hydrocarbon receptor ligand, suppresses tumor metastasis in vitro and in vivo.

Estrogen receptor (ER)­negative breast tumors are associated with low survival rates, which is related to their ability to grow and metastasize into distal organs. The aryl hydrocarbon receptor (AhR), a ligand­activated transcription factor that is involved in several biological processes, is a promising anti­metastatic target. Luteolin, a non­toxic naturally occurring plant flavonoid with diverse biological activities, has been demonstrated to be effective against certain types of cancer, and has also been described as a ligand of AhR. In the present study, various cancer cell lines were first investigated following treatment with luteolin, and luteolin exhibited the lowest IC50 in MDA­MB­231 cells. Then, the efficiency of luteolin in suppressing the metastasis of ER­negative breast cancer in vitro was assessed. MDA­MB­231 cells were treated with luteolin in vitro. Subsequently, MTT assay and flow cytometry were used to detect cell viability, the cell cycle and apoptosis, and a Transwell assay was used to evaluate cell invasion. In addition, reverse transcription­semi­quantitative PCR and western blot were performed to detect the mRNA and protein expression levels of matrix metalloproteinase (MMP)­2 and MMP­9. In addition, the number of surface tumor nodules was measured in vivo, in mice bearing B16­F10 tumors, following treatment with luteolin. Luteolin inhibited the viability and induced the apoptosis of MDA­MB­231 cells, which was accompanied by cell cycle arrest. This was associated with a decrease in the expression of the pro­metastatic markers C­X­C chemokine receptor type 4 (CXCR4), MMP­2 and MMP­9, which was reversed by AhR inhibition. Furthermore, it was identified that luteolin could inhibit the metastasis in a B16F10 mouse xenograft model, and the levels of MMP­9, MMP­2 and CXCR4 were significantly decreased in the lung tissues isolated from tumor­bearing nude mice following luteolin treatment. In conclusion, luteolin is a potential molecule for inhibiting breast cancer invasion and metastasis, which could have promising clinical applications.