Complete synchronization of three-layer Rulkov neuron network coupled by electrical and chemical synapses.

This paper analyzes the complete synchronization of a three-layer Rulkov neuron network model connected by electrical synapses in the same layers and chemical synapses between adjacent layers. The outer coupling matrix of the network is not Laplacian as in linear coupling networks. We develop the master stability function method, in which the invariant manifold of the master stability equations (MSEs) does not correspond to the zero eigenvalues of the connection matrix. After giving the existence conditions of the synchronization manifold about the nonlinear chemical coupling, we investigate the dynamics of the synchronization manifold, which will be identical to that of a synchronous network by fixing the same parameters and initial values. The waveforms show that the transient chaotic windows and the transient approximate periodic windows with increased or decreased periods occur alternatively before asymptotic behaviors. Furthermore, the Lyapunov exponents of the MSEs indicate that the network with a periodic synchronization manifold can achieve complete synchronization, while the network with a chaotic synchronization manifold can not. Finally, we simulate the effects of small perturbations on the asymptotic regimes and the evolution routes for the synchronous periodic and the non-synchronous chaotic network.

Study on landslide susceptibility mapping with different factor screening methods and random forest models.

The number of input factors affects the prediction accuracy of a model. Factor screening plays an important role as the starting point for data input. The aim of this study is to explore the influence of different factor screening methods on the prediction results. Taking the 2014 landslide inventory of Jingdong County as an example, a landslide database was constructed based on 136 landslide events and 11 selected factors, which were randomly divided into a training dataset and a test dataset according to a ratio of 7:3. Four factor screening methods, namely, the information gain ratio (IGR), GeoDetector, Pearson correlation coefficient and multicollinearity test (MT), were selected to screen the factors. A random forest (RF) model was then used in combination with each factor set for landslide susceptibility mapping (LSM). Finally, accuracy validation was performed using confusion matrices and ROC curves. The results show that factor screening is beneficial in improving the accuracy of the resulting model compared to the original model. Second, the IGR_RF model had the highest AUC value (0.9334), which was higher than that of the MT_RF model without factor screening (0.9194), and the IGR_RF model predicted the most landslides in the very high susceptibility zone (51.22%), indicating the good prediction performance of the IGR_RF model. Finally, the factor weighting analysis revealed that NDVI, elevation and aspect had the greatest influence on landslides in Jingdong County and that curvature had the least influence on landslides. This study can provide a reference for factor screening in LSM.

Corrigendum: Different immunological mechanisms between AQP4 antibody-positive and MOG antibody-positive optic neuritis based on RNA sequencing analysis of whole blood.

[This corrects the article DOI: 10.3389/fimmu.2023.1095966.].

A Residual UNet Denoising Network Based on Multi-Scale Feature Extraction and Attention-Guided Filter.

In order to obtain high-quality images, it is very important to remove noise effectively and retain image details reasonably. In this paper, we propose a residual UNet denoising network that adds the attention-guided filter and multi-scale feature extraction blocks. We design a multi-scale feature extraction block as the input block to expand the receiving domain and extract more useful features. We also develop the attention-guided filter block to hold the edge information. Further, we use the global residual network strategy to model residual noise instead of directly modeling clean images. Experimental results show our proposed network performs favorably against several state-of-the-art models. Our proposed model can not only suppress the noise more effectively, but also improve the sharpness of the image.

Different immunological mechanisms between AQP4 antibody-positive and MOG antibody-positive optic neuritis based on RNA sequencing analysis of whole blood.

Purpose: To compare the different immunological mechanisms between aquaporin 4 antibody-associated optic neuritis (AQP4-ON) and myelin oligodendrocyte glycoprotein antibody-associated optic neuritis (MOG-ON) based on RNA sequencing (RNA-seq) of whole blood. Methods: Whole blood was collected from seven healthy volunteers, 6 patients with AQP4-ON and 8 patients with MOG-ON, and used for RNA-seq analysis. An examination of immune cell infiltration was performed using the CIBERSORTx algorithm to identify infiltrated immune cells. Results: RNA-seq analysis showed that the inflammatory signaling was mainly activated by TLR2, TLR5, TLR8 and TLR10 in AQP4-ON patients, while which was mainly activated by TLR1, TLR2, TLR4, TLR5 and TLR8 in MOG-ON patients. Biological function identification of differentially expressed genes (DEGs) based on Gene Ontology (GO) term and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, as well as Disease Ontology (DO) analysis, showed that the inflammation in AQP4-ON was likely mediated by damage-associated molecular pattern (DAMP), while which in MOG-ON was likely mediated by pathogen-associated molecular pattern (PAMP). Analysis of immune cell infiltration showed that the proportion of immune cell infiltration was related to patients' vision. The infiltration ratios of monocytes (rs=0.69, P=0.006) and M0 macrophages (rs=0.66, P=0.01) were positively correlated with the BCVA (LogMAR), and the infiltration ratio of neutrophils was negatively correlated with the BCVA (LogMAR) (rs=0.65, P=0.01). Conclusion: This study reveals different immunological mechanisms between AQP4-ON and MOG-ON based on transcriptomics analysis of patients' whole blood, which may expand the current knowledge regarding optic neuritis.

ASK1/p38­mediated NLRP3 inflammasome signaling pathway contributes to aberrant retinal angiogenesis in diabetic retinopathy.

Diabetic retinopathy (DR) is the leading cause of blindness among the working­age population in several countries. Despite the available treatments, some patients are diagnosed at the late stages of the disease when treatment is more difficult. Hence, it is crucial that novel targets are identified in order to improve the clinical therapy of DR. In the present study, an animal model of DR and a cell model using primary human retinal microvascular endothelial cells exposed to high glucose were constructed to examine the association between apoptosis signal­regulating kinase 1 (ASK1)/p38 and NLR family pyrin domain containing 3 (NLRP3) in DR. The results revealed that DR induced inflammatory response and microvascular cell proliferation. NLRP3 contributed to DR­mediated inflammatory development and progression, which promoted the expression of inflammatory­related cytokines. In addition, NLRP3 promoted the tube formation of retinal microvascular endothelial cells and angiogenesis. Moreover, further research indicated that the NLRP3­mediated aberrant retinal angiogenesis in DR was regulated by ASK1 and p38. It was thus suggested that ASK1/p38 may be novel target for the treatment of DR.

p38 promoted retinal micro-angiogenesis through up-regulated RUNX1 expression in diabetic retinopathy.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and is characterized by visible microvascular alterations including retinal ischemia-reperfusion injury, inflammation, abnormal permeability, neovascularization and macular edema. Despite the available treatments, some patients present late in the course of the disease when treatment is more difficult. Hence, it is crucial that the new targets are found and utilized in the clinical therapy of DR. In the present study, we constructed a DR animal model and a model in HRMECs to investigate the relationship between p38 and RUNX1 in retinal micro-angiogenesis in diabetic retinopathy. We found that p38 could promote retinal micro-angiogenesis by up-regulating RUNX1 expression in diabetic retinopathy. This suggested that the p38/ RUNX1 pathway could become a new retinal micro-angiogenesis target in DR treatment.

Targeting Keap1 by miR-626 protects retinal pigment epithelium cells from oxidative injury by activating Nrf2 signaling.

Activation of the NF-E2-related factor 2 (Nrf2) cascade can offer significant protection against oxidative stress in retinal pigment epithelium (RPE) cells. Here, we identified a novel kelch-like ECH-associated protein 1 (Keap1)-targeting microRNA, microRNA-626 (miR-626) that activates Nrf2 signaling. In ARPE-19 cells and primary human RPE cells, ectopic overexpression of miR-626 targeting the 3'-UTR (3'-untranslated region) of Keap1 downregulated its expression, promoting Nrf2 protein stabilization and nuclear translocation, leading to expression of ARE-dependent genes (HO1, NOQ1 and GCLC). Functional studies showed that miR-626 protected RPE cells from hydrogen peroxide (H2O2)-induced oxidative injury. Conversely, miR-626 inhibition induced Keap1 upregulation and Nrf2 cascade inhibition, exacerbating oxidative injury in RPE cells. Further studies demonstrated that miR-626 was ineffective in Keap1-knockout or Nrf2-knockout RPE cells. Importantly, miR-626 also activated Keap1-Nrf2 signaling cascade in human lens epithelial cells (HLECs) and primary human retinal ganglion cells (RGCs), providing protection from H2O2. At last, we show that plasma miR-626 levels are significantly downregulated in age-related macular degeneration (AMD) patients than those in the healthy donors. We conclude that targeting Keap1 by miR-626 protects RPE cells and other ophthalmic cells from oxidative injury via activation of Nrf2 signaling cascade.

AMPKα phosphatase Ppm1E upregulation in human gastric cancer is required for cell proliferation.

Activation of AMP-activated protein kinase (AMPK) is a valuable anti-cancer strategy. In the current study, we tested expression and potential function of Ca2+/calmodulin-dependent protein kinase phosphatase (Ppm1E), an AMPKα phosphatase, in human gastric cancers. Ppm1E expression was elevated in human gastric cancer tissues (vs. normal tissues), which was correlated with AMPK (p-AMPKα, Thr-172) dephosphorylation and mTOR complex 1 (mTORC1) activation. Ppm1E upregulation, AMPK inhibition and mTORC1 activation were also observed in human gastric cancer cell lines (AGS, HGC-27, and SNU601). Intriguingly, Ppm1E knockdown by shRNA induced AMPK activation, mTORC1 inactivation, and proliferation inhibition in AGS cells. On the other hand, forced over-expression of Ppm1E induced further AMPK inhibition and mTORC1 activation to enhance AGS cell proliferation. Remarkably, microRNA-135b-5p ("miR-135b-5p"), an anti-Ppm1E microRNA, was downregulated in both human gastric cancer tissues and cells. Reversely, miR-135b-5p exogenous expression caused Ppm1E depletion, AMPK activation, and AGC cell proliferation inhibition. Together, Ppm1E upregulation in human gastric cancer is important for cell proliferation, possible via regulating AMPK-mTOR signaling.

3D-Printed Ultratough Hydrogel Structures with Titin-like Domains.

Titin is composed of repeated modular domains which unfold and dissipate energy upon loading. Here we employed such molecular-level paradigm to fabricate macroscopic ultratough hydrogel structures with titin-like domains, enabled by three-dimensional printing with multiple nozzles. Under stretch, the relatively thin and weak gel fibers in the printed structures break first and the hidden lengths postpone the failure of the main structures, mimicking the toughening principle in titin. These titin-like folded domains have been incorporated into a synthetic spider-web, which shows significantly enhanced extensibility and toughness. This work provides a new avenue of topological design for materials/structures with desired properties.

miRNA-141 attenuates UV-induced oxidative stress via activating Keap1-Nrf2 signaling in human retinal pigment epithelium cells and retinal ganglion cells.

Activation of NF-E2-related factor 2 (Nrf2) signaling could protect cells from ultra violet (UV) radiation. We aim to provoke Nrf2 activation via downregulating its inhibitor Keap1 by microRNA-141 ("miR-141"). In both human retinal pigment epithelium cells (RPEs) and retinal ganglion cells (RGCs), forced-expression of miR-141 downregulated Keap1, causing Nrf2 stabilization, accumulation and nuclear translocation, which led to transcription of multiple antioxidant-responsive element (ARE) genes (HO1, NOQ1 and GCLC). Further, UV-induced reactive oxygen species (ROS) production and cell death were significantly attenuated in miR-141-expressing RPEs and RGCs. On the other hand, depletion of miR-141 via expressing its inhibitor antagomiR-141 led to Keap1 upregulation and Nrf2 degradation, which aggravated UV-induced death of RPEs and RGCs. Significantly, Nrf2 shRNA knockdown almost abolished miR-141-mediated cytoprotection against UV in RPEs. These results demonstrate that miR-141 targets Keap1 to activate Nrf2 signaling, which protects RPEs and RGCs from UV radiation.

3D Printing of Ultratough Polyion Complex Hydrogels.

Polyion complex (PIC) hydrogels have been proposed as promising engineered soft materials due to their high toughness and good processability. In this work, we reported manufacturing of complex structures with tough PIC hydrogels based on three-dimensional (3D) printing technology. The strategy relies on the distinct strength of ionic bonding in PIC hydrogels at different stages of printing. In concentrated saline solution, PIC forms viscous solution, which can be directly extruded out of a nozzle into water, where dialyzing out of salt and counterions results in sol-gel transition to form tough physical PIC gel with intricate structures. The printability of PIC solutions was systematically investigated by adjusting the PIC material formula and printing parameters in which proper viscosity and gelation rate were found to be key factors for successful 3D printing. Uniaxial tensile tests were performed to printed single fibers and multilayer grids, both exhibiting distinct yet controllable strength and toughness. More complex 3D structures with negative Poisson's ratio, gradient grid, and material anisotropy were constructed as well, demonstrating the flexible printability of PIC hydrogels. The methodology and capability here provide a versatile platform to fabricate complex structures with tough PIC hydrogels, which should broaden the use of such materials in applications such as biomedical devices and artificial tissues.

Squamosamide derivative FLZ protects retinal pigment epithelium cells from oxidative stress through activation of epidermal growth factor receptor (EGFR)-AKT signaling.

Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the pro-survival effect of FLZ in oxidative stressed-RPE cells and studied the underlying signaling mechanisms. Our results showed that FLZ attenuated hydrogen peroxide (H2O2)-induced viability decrease and apoptosis in the RPE cell line (ARPE-19 cells) and in primary mouse RPE cells. Western blotting results showed that FLZ activated AKT signaling in RPE cells. The AKT-specific inhibitor, MK-2206, the phosphoinositide 3-kinase (PI3K)/AKT pan inhibitor, wortmannin, and AKT1-shRNA (short hairpin RNA) depletion almost abolished FLZ-mediated pro-survival/anti-apoptosis activity. We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ-induced AKT activation and the pro-survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H2O2 was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown. In conclusion, FLZ protects RPE cells from oxidative stress through activation of EGFR-AKT signaling, and our results suggest that FLZ might have therapeutic values for AMD.

Alpha-melanocyte stimulating hormone protects retinal pigment epithelium cells from oxidative stress through activation of melanocortin 1 receptor-Akt-mTOR signaling.

Patients with age related macular degeneration (AMD) will develop vision loss in the center of the visual field. Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is an important contributor of AMD. In this study, we explored the pro-survival effect of α-melanocyte stimulating hormone (α-MSH) on oxidative stressed RPE cells. We found that α-MSH receptor melanocortin 1 receptor (MC1R) was functionally expressed in primary and transformed RPE cells. RPE cells were response to α-MSH stimulation. α-MSH activated Akt/mammalian target of rapamycin (mTOR) and Erk1/2 signalings in RPE cells, which were inhibited by MC1R siRNA knockdown. α-MSH protected RPE cells from hydrogen peroxide (H2O2)-induced apoptosis, an effect that was almost abolished when MC1R was depleted by siRNA. α-MSH-mediated S6K1 activation and pro-survival effect against H2O2 was inhibited by Akt inhibitors (perifosine, MK-2206 and LY294002). Further, mTOR inhibition by rapamycin, or by mTOR siRNA knockdown, diminished α-MSH's pro-survival effect in RPE cells. Thus, Akt and its downstream mTOR signaling mediates α-MSH-induced survival in RPE cells. In summary, we have identified a new α-MSH-MC1R physiologic pathway that reduces H2O2-induced RPE cell damage, and might minimize the risk of developing AMD.

Ultraviolet (UV) and hydrogen peroxide activate ceramide-ER stress-AMPK signaling axis to promote retinal pigment epithelium (RPE) cell apoptosis.

Ultraviolet (UV) radiation and reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelium (RPE) cells by inducing cell apoptosis, which is the main cause of age-related macular degeneration (AMD). The mechanism by which UV/ROS induces RPE cell death is not fully addressed. Here, we observed the activation of a ceramide-endoplasmic reticulum (ER) stress-AMP activated protein kinase (AMPK) signaling axis in UV and hydrogen peroxide (H2O2)-treated RPE cells. UV and H2O2 induced an early ceramide production, profound ER stress and AMPK activation. Pharmacological inhibitors against ER stress (salubrinal), ceramide production (fumonisin B1) and AMPK activation (compound C) suppressed UV- and H2O2-induced RPE cell apoptosis. Conversely, cell permeable short-chain C6 ceramide and AMPK activator AICAR (5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide) mimicked UV and H2O2's effects and promoted RPE cell apoptosis. Together, these results suggest that UV/H2O2 activates the ceramide-ER stress-AMPK signaling axis to promote RPE cell apoptosis.

Molecular cloning and characterization of a novel splice variant of the LIM domain family gene, PINCH 2, in human testis.

By hybridizing human adult testis cDNA microarrays with human adult and embryo testis cDNA probes, we identified a novel human testis gene, PINCH 2. PINCH 2 expression was 3.4-fold higher in adult than in fetal testis. The full length of its cDNA was 963 bp, with a 354-bp open reading frame (ORF), encoding a 117-amino acid protein. PINCH 2 was a splicing isoform of PINCH. It shared one exon, which encoded the LIM domain, with PINCH gene in human genome. Multitissue reverse transcriptase-polymerase chain reaction (RTPCR) analysis revealed that this gene was expressed variably in a wide range of tissues, with high expression levels in human adult testis. These results suggest that PINCH 2, a novel LIM domain-containing gene, may play an important role in testicular development/spermatogenesis.