Subretinal fibrosis secondary to neovascular age-related macular degeneration: mechanisms and potential therapeutic targets.

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and choroidal vessels, which leads to permanent central vision loss of patients with neovascular age-related macular degeneration. The pathogenesis of subretinal fibrosis is complex, and the underlying mechanisms are largely unknown. Therefore, there are no effective treatment options. A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments. The current article reviews several aspects of subretinal fibrosis, including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis; multimodal imaging techniques for subretinal fibrosis; animal models for studying subretinal fibrosis; cellular and non-cellular constituents of subretinal fibrosis; pathophysiological mechanisms involved in subretinal fibrosis, such as aging, infiltration of macrophages, different sources of mesenchymal transition to myofibroblast, and activation of complement system and immune cells; and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis, such as vascular endothelial growth factor, connective tissue growth factor, fibroblast growth factor 2, platelet-derived growth factor and platelet-derived growth factor receptor-ß, transforming growth factor-ß signaling pathway, Wnt signaling pathway, and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10. This review will improve the understanding of the pathogenesis of subretinal fibrosis, allow the discovery of molecular targets, and explore potential treatments for the management of subretinal fibrosis.

Microvascular destabilization and intricated network of the cytokines in diabetic retinopathy: from the perspective of cellular and molecular components.

Microvascular destabilization is the primary cause of the inner blood-retinal barrier (iBRB) breakdown and increased vascular leakage in diabetic retinopathy (DR). Microvascular destabilization results from the combinational effects of increased levels of growth factors and cytokines, involvement of inflammation, and the changed cell-to-cell interactions, especially the loss of endothelial cells and pericytes, due to hyperglycemia and hypoxia. As the manifestation of microvascular destabilization, the fluid transports via paracellular and transcellular routes increase due to the disruption of endothelial intercellular junctional complexes and/or the altered caveolar transcellular transport across the retinal vascular endothelium. With diabetes progression, the functional and the structural changes of the iBRB components, including the cellular and noncellular components, further facilitate and aggravate microvascular destabilization, resulting in macular edema, the neuroretinal damage and the dysfunction of retinal inner neurovascular unit (iNVU). Although there have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying the microvascular destabilization, some still remain to be fully elucidated. Recent data indicate that targeting the intricate signaling pathways may allow to against the microvascular destabilization. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in the microvascular destabilization in DR. In this review, we discuss: (1) the brief introduction of DR and microvascular destabilization; (2) the cellular and molecular components of iBRB and iNVU, and the breakdown of iBRB; (3) the matrix and cell-to-cell contacts to maintain microvascular stabilization, including the endothelial glycocalyx, basement membrane, and various cell-cell interactions; (4) the molecular mechanisms mediated cell-cell contacts and vascular cell death; (5) the altered cytokines and signaling pathways as well as the intricate network of the cytokines involved in microvascular destabilization. This comprehensive review aimed to provide the insights for microvascular destabilization by targeting the key molecules or specific iBRB cells, thus restoring the function and structure of iBRB and iNVU, to treat DR.

Time-varying metasurface driven broadband radar jamming and deceptions.

Conventional radar jamming and deception systems typically necessitate the custom design of complex circuits and algorithms to transmit an additional radio signal toward a detector. Consequently, they are often cumbersome, energy-intensive, and difficult to operate in broadband electromagnetic environment. With the ongoing trend of miniaturization of various devices and the improvement of radar system performance, traditional techniques no longer meet the requirements for broadband, seamless integration, and energy efficiency. Time-varying metasurfaces, capable of manipulating electromagnetic parameters in both temporal and spatial domains, have thus inspired many contemporary research studies to revisit established fields. In this paper, we introduce a time-varying metasurface driven radar jamming and deception system (TVM-RJD), which can perfectly overcome the aforementioned intrinsic challenges. Leveraging a programmable bias voltage, the TVM-RJD can alter the spectrum distribution of incident waves, thereby deceiving radar into making erroneous judgments about the target's location. Experimental outcomes affirm that the accuracy deviation of the TVM-RJD system is less than 0.368 meters, while achieving a remarkable frequency conversion efficiency of up to 96.67%. The TVM-RJD heralds the expansion into a wider application of electromagnetic spatiotemporal manipulation, paving the way for advancements in electromagnetic illusion, radar invisibility, etc.

Rod-Shaped Hemoglobin Crystals: Clues to the Diagnosis of Hemoglobin C Disease.

The typical rod-shaped HbC crystals in the peripheral blood smear often provide the diagnostic clue to the HbC disease. This case highlights that a careful review of blood film morphology may be helpful to detect HbC disease, although this case's routine blood test is normal and do not meet the rules of re-examinations.

Enhancing Precision in Cardiac Segmentation for MR-Guided Radiation Therapy through Deep Learning.

INTRODUCTION: Cardiac substructure dose metrics are more strongly linked to late cardiac morbidities than whole-heart metrics. MR-guided radiation therapy (MRgRT) enables substructure visualization during daily localization, allowing potential for enhanced cardiac sparing. We extend a publicly available state-of-the-art deep learning (DL) framework, nnU-Net, to incorporate self-distillation (nnU-Net.wSD) for substructure segmentation for MRgRT. METHODS: Eighteen (Institute A) patients who underwent thoracic or abdominal radiation therapy on a 0.35 T MR-guided linac were retrospectively evaluated. On each image, one of two radiation oncologists delineated reference contours of 12 cardiac substructures (chambers, great vessels, and coronary arteries) used to train (n=10), validate (n=3), and test (n=5) nnU-Net.wSD leveraging a teacher-student network and comparing to standard 3D U-Net. The impact of using simulation data or including 3-4 daily images for augmentation during training was evaluated for nnU-Net.wSD. Geometric metrics (Dice similarity coefficient (DSC), mean distance to agreement (MDA), and 95% Hausdorff distance (HD95)), visual inspection, and clinical dose volume histograms (DVHs) were evaluated. To determine generalizability, Institute A's model was tested on an unlabeled dataset from Institute B (n=22) and evaluated via consensus scoring and volume comparisons. RESULTS: nnU-Net.wSD yielded a DSC (reported mean ± standard deviation) of 0.65±0.25 across the 12 substructures (Chambers: 0.85±0.05, Great Vessels: 0.67±0.19, and Coronary Arteries 0.33±0.16, mean MDA <3 mm, and mean HD95 <9 mm) while outperforming the 3D U-Net (0.583±0.28, p<0.01). Leveraging fractionated data for augmentation improved over a single MR-SIM timepoint (0.579±0.29, p<0.01). Predicted contours yielded DVHs that closely matched the clinical treatment plans where mean and D0.03cc doses deviated by 0.32±0.5 Gy and 1.42±2.6 Gy respectively. No statistically significant differences between Institute A and B volumes (p>0.05) for 11 of 12 substructures with larger volumes requiring minor changes and coronary arteries exhibiting more variability. CONCLUSIONS: This work is a critical step to rapid and reliable cardiac substructure segmentation to improve cardiac sparing in low-field MRgRT.

ANGPTL3 accelerates atherosclerotic progression via direct regulation of M1 macrophage activation in plaque.

INTRODUCTION: The N-terminal domain of angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity. Its C-terminal fibrinogen-like (FBN) domain is a ligand of macrophage integrin αvß3. OBJECTIVES: ANGPTL3 might home to plaque where it directly regulates macrophage function via integrin αvß3 for atherosclerosis progression. METHODS: Ldlr-/- mice on a high-fat diet and ApoE-/- mice on a chow diet were received adeno-associated virus (AAV)-mediated Angptl3 gene transfer and followed up for 12 weeks. ApoE-/- mice were injected AAV containing FLAG-tagged Angptl3 cDNA for tracing. Atherosclerotic features were compared between Angptl3-/-ApoE-/- mice and ApoE-/- littermates. THP-1 cells were exposed to 0 or 50 µg/ml ANGPTL3 FBN domain for 24 h to evaluate Toll-like receptor (TLR)4 expression using western blot analysis and circulating cytokine and chemokine profiles by the MILLIPLEX MAP assay. Phospho-proteomic profile was established in ANGPTL3-treated macrophages. Integrin ß3 deficient THP-1 cells were obtained by sgRNAs targeting RGD sequence using Lentivirus-Cas9 system. RESULTS: Angptl3 overexpression increased atherosclerotic progression and CD68+ macrophages in plaque (p < 0.05 for all). By immunostaining, FLAG+ cells were identified in plaque of gene transferred ApoE-/- mice. Fluorescent immunostaining detected co-localisation of Angptl3 and CD68 in plaque macrophages. Phospho-proteomic analysis revealed that Angptl3 induced phosphorylation of proteins that were involved in the IL-17 signalling pathway in THP-1 cells. In vitro, ANGPTL3 treatment increased the production of interleukin (IL)-1ß and tumour necrosis factor-α in THP-1 cells (p < 0.05 for both). Exposure of ANGPTL3 to THP-1 cells induced Akt phosphorylation which was weakened in integrin ß3 deficient ones. ANGPTL3 elevated TLR4 expression via Akt phosphorylation. In response to lipopolysaccharide, nuclear factor-κB activity was 2.2-fold higher in THP-1 cells pre-treated with ANGPTL3 than in untreated cells (p < 0.05). CONCLUSIONS: Targeting ANGPTL3 could yield a dual benefit of lowering lipid levels in the blood and suppressing macrophage activation in plaque.

[Effect of CircCCND1 on the Malignant Biological Behaviors of H446 Lung Cancer Cells by Regulating the MiR-340-5p/TGIF1 Axis].

BACKGROUND: Lung cancer is a common malignant tumor of the lung. To explore the molecular mechanism of the occurrence and development of lung cancer is a hot topic in current research. Cyclic RNA D1 (CircCCND1) is highly expressed in lung cancer and may be a potential target for the treatment of lung cancer. The aim of this study was to investigate the effect of CircCCND1 on the malignant biological behaviors of lung cancer cells by regulating the miR-340-5p/transforming growth factor ß-induced factor homeobox 1 (TGIF1) axis. METHODS: The expression of CircCCND1, miR-340-5p, and TGIF1 mRNA in human normal lung epithelial cells BEAS-2B and human lung cancer H446 cells were detected. H446 cells cultured in vitro were randomly divided into control group, CircCCND1 siRNA group, miR-340-5p mimics group, negative control group, and CircCCND1 siRNA+miR-340-5p inhibitor group. Cell proliferation, mitochondrial membrane potential, apoptosis, migration, and invasion were detected, and the expressions of CircCCND1, miR-340-5p, TGIF1 mRNA, BCL2-associated X protein (Bax), cleaved Caspase-3, N-cadherin, E-cadherin, and TGIF1 proteins in each group were detected. The targeting relationship of miR-340-5p with CircCCND1 and TGIF1 was verified. RESULTS: Compared with BEAS-2B cells, CircCCND1 and TGIF1 mRNA were increased in H446 cells, and miR-340-5p expression was decreased (P<0.05). Knocking down CircCCND1 or up-regulating the expression of miR-340-5p inhibited the proliferation, migration and invasion of H446 cells, decreased the expression of TGIF1 mRNA and TGIF1 protein, and promoted cell apoptosis. Down-regulation of miR-340-5p could antagonize the inhibitory effect of CircCCND1 knockdown on the malignant biological behavior of H446 lung cancer cells. CircCCND1 may target the down-regulation of miR-340-5p, and miR-340-5p may target the down-regulation of TGIF1. CONCLUSIONS: Knocking down CircCCND1 can inhibit the malignant behaviors of lung cancer H446 cells, which may be achieved through the regulation of miR-340-5p/TGIF1 axis.

Association Between Atherogenic Index of Plasma and Risk of Incident Major Adverse Cardiovascular Events.

It is unclear whether the atherogenic index of plasma (AIP) is associated with major adverse cardiovascular events (MACEs) in the general population. A total of 361,644 participants (aged 56.19 ± 8.09 years; 44.79% male) free of a history of MACEs at baseline from the UK Biobank data were included in the analysis. The AIP was calculated using log (triglyceride/high-density lipoprotein-cholesterol). Over a mean follow-up of 12.19 ± 1.60 years, 16,683 participants developed MACEs. After adjustment for traditional risk factors, each 1 unit increase in AIP was associated with a 45.3% higher risk of incident MACEs (hazard ratio (HR), 1.453 [95% confidence interval (CI) 1.371-1.540], P < 0.001). Results were similar when individuals were categorized by the AIP quartiles (HR, 1.283 [95% CI 1.217-1.351]; comparing extreme quartiles). The subgroup analyses showed that the association between AIP and risk of incident MACEs was more obvious in female participants who are < 60 years old and free of hypertension or diabetes. Sensitivity analysis included participants without any lipid-lowering medication or excluded incident MACEs in the first 2 years of follow-up confirming the robustness of the findings. Elevated AIP is a risk factor of incident MACEs in the general population, independent of traditional risk factors.Dynamic monitoring of the AIP may help select the population at high risk of cardiovascular events and guide primary prevention.

Dysregulation of circulating T follicular helper cell subsets and their potential role in the pathogenesis of syphilis.

Introduction: The role of the host immune response could be critical in the development of Treponema pallidum (Tp) infection in individuals with latent syphilis. This study aims to investigate the alterations in T follicular helper T (Tfh) cell balance among patients with secondary syphilis and latent syphilis. Methods: 30 healthy controls (HCs), 24 secondary syphilis patients and 41 latent syphilis patients were enrolled. The percentages of total Tfh, ICOS+ Tfh, PD-1+ Tfh, resting Tfh, effector Tfh, naïve Tfh, effector memory Tfh, central memory Tfh,Tfh1, Tfh2, and Tfh17 cells in the peripheral blood were all determined by flow cytometry. Results: The percentage of total Tfh cells was significantly higher in secondary syphilis patients compared to HCs across various subsets, including ICOS+ Tfh, PD-1+ Tfh, resting Tfh, effector Tfh, naïve Tfh, effector memory Tfh, central memory Tfh, Tfh1, Tfh2, and Tfh17 cells. However, only the percentages of ICOS+ Tfh and effector memory Tfh cells showed significant increases in secondary syphilis patients and decreases in latent syphilis patients. Furthermore, the PD-1+ Tfh cells, central memory Tfh cells, and Tfh2 cells showed significant increases in latent syphilis patients, whereas naïve Tfh cells and Tfh1 cells exhibited significant decreases in secondary syphilis patients when compared to the HCs. However, no significant change was found in resting Tfh and effector Tfh in HCs and secondary syphilis patients or latent syphilis patients. Discussion: Dysregulated ICOS+ Tfh or effector memory Tfh cells may play an important role in immune evasion in latent syphilis patients.

An interventional study of baicalin on neuronal pentraxin-1, neuronal pentraxin-2, and C-reactive protein in Alzheimer's disease rat model.

Background: Baicalin has been shown to promote spatial learning and neural regeneration, which might increase the differentiation of neural stem cells in Alzheimer's disease (AD) rat models. We aimed to study the role of baicalin on neuronal pentraxin-1 (NPTX-1), neuronal pentraxin-2 (NPTX-2), and C-reactive protein (CRP) in AD model rats. Methods: The 30 male Sprague Dawley rats were divided into three groups: the control group, the AD model group, and the AD + baicalin group. Then, the Morris water maze was used to verify the effect of baicalin on the memory and spatial learning of rats. Immunohistochemistry and immunofluorescence were used to observe the expression of NPTX-1, NPTX-2, and CRP in brain tissue. Results: Compared with the AD model group, the AD rats treated with baicalin spent significantly less time finding escape latencies (P = 0.008) and had longer cross-platform times in the target quadrant (P = 0.015). In addition, the AD + baicalin group had significantly higher numbers of hippocampal neurons compared with the AD model group (P < 0.05). Baicalin also obviously decreased the apoptosis of neurons. Moreover, compared with the AD model group, the NPTX-1 and CRP expression in the AD + baicalin group was significantly reduced (P = 0.000) while the expression of NPTX-2 in the brain tissue of AD rats was significantly increased (P = 0.000). Conclusions: Baicalin can play a therapeutic role by downregulating NPTX-1, upregulating NPTX-2, and downregulating CPR in AD model rats.

Dysregulated Tfr/Tfh2 cells in patients with polycystic ovarian syndrome.

Recent research revealed the pathogenic role of B cells in the pathogenesis of polycystic ovary syndrome (PCOS), while the Tfh cell plays a critical role in the B cell mediated autoantibody production and humoral immunity, but had not been investigated in PCOS patients. The frequency of Tfh and B cell subsets (Tfh1, Tfh2, Tfh17, naïve B, memory B, and plasma cells) in the peripheral blood of 21 PCOS patients and 15 healthy controls were investigated by flow cytometry. And the levels of follicle-stimulating hormone, luteinizing hormone, testosterone, prolactin and estradiol progesterone were measured by using the immunoluminescence method. Also, the associations between these hormone levels and Tfh cell subsets or B cell subsets were analyzed. No significant difference was observed in total Tfh cells between 21 PCOS patients and 15 healthy controls (p > 0.05). But the percentages of Tfh2 and plasma cells were significantly higher in 21 PCOS patients compared to 15 healthy controls (p < 0.05). In contrast, the frequency of Tfr cells and Tfr/Tfh2 ratio were significantly lower than healthy controls (p < 0.01). Importantly, among these cells, only the percentage of Tfh2 cells was positively correlated with the levels of testosterone (r = 0.513, p = 0.018). And the percentage of Tfr cells and Tfr/Tfh2 ratio were also positively correlated with the levels of testosterone (r = 0.567, p = 0.007; r = 0.434, p = 0.05) and prolactin (r = 0.511, p = 0.018; r = 0.490, p = 0.024). These new findings provide unique insights into dysregulated Tfh/Tfr cells in mediating the immunopathogenesis of PCOS patients.

A novel approach to precipitation prediction using a coupled CEEMDAN-GRU-Transformer model with permutation entropy algorithm.

The accurate forecasting of precipitation in the upper reaches of the Yellow River is imperative for enhancing water resources in both the local and broader Yellow River basin in the present and future. While many models exist for predicting precipitation by analyzing historical data, few consider the impact of different frequency sequences on model accuracy. In this study, we propose a coupled monthly precipitation prediction model that leverages the adaptive noise complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN), gated recurrent unit neural network (GRU), and attention mechanism-based transformer model. The permutation entropy (PE) algorithm is employed to partition the data processed by CEEMDAN into different frequencies, with different models utilized to predict different frequencies. The predicted results are subsequently combined to obtain the monthly precipitation prediction value. The model is applied to precipitation prediction in four regions in the upper reaches of the Yellow River and compared with other models. Evaluation results demonstrate that the CEEMDAN-GRU-Transformer model outperforms other models in predicting precipitation for these regions, with a coefficient of determination R2 greater than 0.8. These findings suggest that the proposed model provides a novel and effective method for improving the accuracy of regional medium and long-term precipitation prediction.

A primary amoebic meningoencephalitis case associated with swimming in seawater.

This case report describes a 62-year-old male fisherman who presented with persistent vomiting, headache, and behavior changes. Despite initial antibiotic and corticosteroid treatment, his condition worsened, leading to coma and subsequent death. Macro-genome sequencing of cerebrospinal fluid (CSF) revealed the presence of Naegleria fowleri infection, which had been missed during initial laboratory tests. The patient's exposure history included sea-swimming near Zhoushan Island.

Eye accommodation-inspired neuro-metasurface focusing.

The human eye, which relies on a flexible and controllable lens to focus light onto the retina, has inspired many scientific researchers to understand better and imitate the biological vision system. However, real-time environmental adaptability presents an enormous challenge for artificial eye-like focusing systems. Inspired by the mechanism of eye accommodation, we propose a supervised-evolving learning algorithm and design a neuro-metasurface focusing system. Driven by on-site learning, the system exhibits a rapid response to ever-changing incident waves and surrounding environments without any human intervention. Adaptive focusing is achieved in several scenarios with multiple incident wave sources and scattering obstacles. Our work demonstrates the unprecedented potential for real-time, fast, and complex electromagnetic (EM) wave manipulation for various purposes, such as achromatic, beam shaping, 6 G communication, and intelligent imaging.