Dynamics of antiphase bursting modulated by the inhibitory synaptic and hyperpolarization-activated cation currents.

Antiphase bursting related to the rhythmic motor behavior exhibits complex dynamics modulated by the inhibitory synaptic current (Isyn), especially in the presence of the hyperpolarization-activated cation current (Ih). In the present paper, the dynamics of antiphase bursting modulated by the Ih and Isyn is studied in three aspects with a theoretical model. Firstly, the Isyn and the slow Ih with strong strength are the identified to be the necessary conditions for the antiphase bursting. The dependence of the antiphase bursting on the two currents is different for low (escape mode) and high (release mode) threshold voltages (Vth) of the inhibitory synapse. Secondly, more detailed co-regulations of the two currents to induce opposite changes of the bursting period are obtained. For the escape mode, increase of the Ih induces elevated membrane potential of the silence inhibited by a strong Isyn and shortened silence duration to go beyond Vth, resulting in reduced bursting period. For the release mode, increase of the Ih induces elevated tough value of the former part of the burst modulated by a nearly zero Isyn and lengthen burst duration to fall below Vth, resulting in prolonged bursting period. Finally, the fast-slow dynamics of the antiphase bursting are acquired. Using one-and two-parameter bifurcations of the fast subsystem of a single neuron, the burst of the antiphase bursting is related to the stable limit cycle, and the silence modulated by a strong Isyn to the stable equilibrium to a certain extent. The Ih mainly modulates the dynamics within the burst and quiescent state. Furthermore, with the fast subsystem of the coupled neurons, the silence is associated with the unstable equilibrium point. The results present theoretical explanations to the changes in the bursting period and fast-slow dynamics of the antiphase bursting modulated by the Isyn and Ih, which is helpful for understanding the antiphase bursting and modulating rhythmic motor patterns.

Pattern selection mechanism from the equilibrium point and limit cycle.

The outbreak of infectious diseases often exhibits periodicity, and this periodic behavior can be mathematically represented as a limit cycle. However, the periodic behavior has rarely been considered in demonstrating the cluster phenomenon of infection induced by diffusion (the instability modes) in the SIR model. We investigate the emergence of Turing instability from a stable equilibrium and a limit cycle to illustrate the dynamical and biological mechanisms of pattern formation. We identify the Hopf bifurcation to demonstrate the existence of a stable limit cycle using First Lyapunov coefficient in our spatiotemporal diffusion-driven SIR model. The competition between different instability modes induces different types of patterns and eventually spot patterns emerge as stable patterns. We investigate the impact of susceptible, infected, and recovered individuals on the type of patterns. Interestingly, these instability modes play a vital role in selecting the pattern formations, which is directly related to the number of observed spot patterns. Subsequently, we explain the dynamical and biological mechanisms of spot patterns to develop an effective epidemic prevention strategy.

Bifurcation and pattern dynamics in the nutrient-plankton network.

This paper used a Holling-IV nutrient-plankton model with a network to describe algae's spatial and temporal distribution and variation in a specific sea area. The stability and bifurcation of the nonlinear dynamic model of harmful algal blooms (HABs) were analyzed using the nonlinear dynamic theory and de-eutrophication's effect on algae's nonlinear dynamic behavior. The conditions for equilibrium points (local and global), saddle-node, transcritical, Hopf-Andronov and Bogdanov-Takens (B-T) bifurcation were obtained. The stability of the limit cycle was then judged and the rich and complex phenomenon was obtained by numerical simulations, which revealed the robustness of the nutrient-plankton system by switching between nodes. Also, these results show the relationship between HABs and bifurcation, which has important guiding significance for solving the environmental problems of HABs caused by the abnormal increase of phytoplankton.

Spatiotemporal Patterns in a General Networked Hindmarsh-Rose Model.

Neuron modelling helps to understand the brain behavior through the interaction between neurons, but its mechanism remains unclear. In this paper, the spatiotemporal patterns is investigated in a general networked Hindmarsh-Rose (HR) model. The stability of the network-organized system without delay is analyzed to show the effect of the network on Turing instability through the Hurwitz criterion, and the conditions of Turing instability are obtained. Once the analysis of the zero-delayed system is completed, the critical value of the delay is derived to illustrate the profound impact of the given network on the collected behaviors. It is found that the difference between the collected current and the outgoing current plays a crucial role in neuronal activity, which can be used to explain the generation mechanism of the short-term memory. Finally, the numerical simulation is presented to verify the proposed theoretical results.

Pattern mechanism in stochastic SIR networks with ER connectivity.

The diffusion of the susceptible and infected is a vital factor in spreading infectious diseases. However, the previous SIR networks cannot explain the dynamical mechanism of periodic behavior and endemic diseases. Here, we incorporate the diffusion and network effect into the SIR model and describes the mechanism of periodic behavior and endemic diseases through wavenumber and saddle-node bifurcation. We also introduce the standard network structured entropy (NSE) and demonstrate diffusion effect could induce the saddle-node bifurcation and Turing instability. Then we reveal the mechanism of the periodic outbreak and endemic diseases by the mean-field method. We provide the Turing instability condition through wavenumber in this network-organized SIR model. In the end, the data from COVID-19 authenticated the theoretical results.

Turing pattern induced by the directed ER network and delay.

Infectious diseases generally spread along with the asymmetry of social network propagation because the asymmetry of urban development and the prevention strategies often affect the direction of the movement. But the spreading mechanism of the epidemic remains to explore in the directed network. In this paper, the main effect of the directed network and delay on the dynamic behaviors of the epidemic is investigated. The algebraic expressions of Turing instability are given to show the role of the directed network in the spread of the epidemic, which overcomes the drawback that undirected networks cannot lead to the outbreaks of infectious diseases. Then, Hopf bifurcation is analyzed to illustrate the dynamic mechanism of the periodic outbreak, which is consistent with the transmission of COVID-19. Also, the discrepancy ratio between the imported and the exported is proposed to explain the importance of quarantine policies and the spread mechanism. Finally, the theoretical results are verified by numerical simulation.

Puerarin ameliorates retinal ganglion cell damage induced by retinal ischemia/reperfusion through inhibiting the activation of TLR4/NLRP3 inflammasome.

AIMS: Retinal ischemia/reperfusion (I/R) injury is common in the development of ophthalmic diseases and potentially causes blindness. In present study, the aim is to investigate the possible protective effects of puerarin on retinal I/R. MAIN METHODS: Retinal I/R injury was conducted on the left eyes of male Sprague Dawley rats, which were subsequently received treatment with puerarin. After administration, retinal I/R-induced apoptosis, oxidative stress and inflammatory responses were detected. Meanwhile, we purified retinal ganglion cells (RGCs) from 7-day-old rats. After subjected RGCs to oxygen and glucose deprivation/reoxygenation (OGD/R), apoptosis and TLR4/NLRP3 inflammasome activation in RGCs were detected. KEY FINDINGS: Puerarin prominently suppressed apoptosis, alleviated oxidative stress and suppressed TLR4/NLRP3 inflammasome activation in rats with retinal I/R injury. Consistent with our in vivo study, we found puerarin ameliorated retinal I/R injury through suppressing apoptosis and TLR4/NLRP3 inflammasome activation in RGCs. SIGNIFICANCE: Our findings reveal that puerarin plays a protective role against retinal I/R injury by alleviating RGC damage, and is beneficial for the treatment of I/R injury-caused ophthalmic diseases.

Rho Kinase Type 1 (ROCK1) Promotes Lipopolysaccharide-induced Inflammation in Corneal Epithelial Cells by Activating Toll-Like Receptor 4 (TLR4)-Mediated Signaling.

BACKGROUND Rho kinases (ROCKs) are the typical downstream effectors of RhoA, which can regulate corneal epithelial wound healing. In this study, the role of ROCK1 in lipopolysaccharide (LPS)-induced cornea inflammation was investigated. MATERIAL AND METHODS The expression of ROCK1 in human corneal epithelial cells (HCECs) was bilaterally modulated with ROCK1 expression vector and ROCK1 inhibitor Y-27632. The effects of ROCK1 modulation on the inflammatory response, cell viability, cell apoptosis, and cell cycle distribution were detected by ELISA assay, MTT assay, and flow cytometry, respectively. The pathways involved in the effect of ROCK1 in HCECs was preliminarily explained by detecting changes of TLR4-mediated NF-kB and ERK signaling using western blotting and electrophoretic mobility shift assays. RESULTS Overexpression of ROCK1 promoted LPS-induced production of IL-6, IL-8, IL-1ß, and TNF-α, and the apoptotic process in HCECs. Augmented inflammation and apoptosis were associated with stronger activation of TLR4-mediated signal transduction; the phosphorylation of IkBa, JNK, ERK1/2, and p38, and nuclear translocation of NF-κB p65 induced by LPS were further increased by overexpression of ROCK1. Inhibition of ROCK1 function by Y-27632 blocked the effect of LPS on HCECs; both LPS-induced inflammation and apoptosis was alleviated by Y-27632, which was associated with suppression of TLR4-mediated NF-κB and ERK signaling. CONCLUSIONS LPS-induced inflammation and apoptosis in HCECs depended on the function of ROCK1, inhibition of which would attenuate impairments on cornea cells due to LPS.

Differential proteomic analyses of cataracts from rat models of type 1 and 2 diabetes.

PURPOSE: To identify differential changes in proteins and metabolites underlying "fast" type 1 (T1DC) and "slow" type 2 (T2DC) diabetic cataract (DC) formation in rat. METHODS: Rat models of types 1 and 2 diabetes consisted of streptozotocin injection without and with high-fat diet, respectively. Cataract progression was examined weekly. At week 6, total protein changes were comparatively and quantitatively assessed by two-dimensional differential in-gel electrophoresis (2-D DIGE) coupled with mass spectrometry, and relevant metabolic changes were examined. Differences in high molecular weight (HMW) crystallin species between diabetic and control lenses were similarly identified. RESULTS: Cataracts were morphologically different and progressed more slowly in T2DC versus T1DC. αA-crystallin, ßB2-crystallin, and ßA4-crystallin were significantly decreased in both DC types versus control. αB-crystallin was increased while ßB1-crystallin was markedly decreased in T2DC. In T1DC, γB-crystallin and γS-crystallin fragmentation were increased. High-fat diet by itself had little impact, except for lowering γS-crystallin fragmentation. Despite significantly decreased opacity, a greater decrease in intermediate filaments (IFs) and more HMW crystallin species were observed in T2DC versus T1DC. However, aldose reductase expression and activity and sorbitol levels were increased to a greater extent in T1DC, while reduced glutathione (GSH) and reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) levels were decreased to a greater extent and adenosine triphosphate (ATP) level was much lower in T1DC versus T2DC. CONCLUSIONS: The results suggest that osmotic damage, GSH loss, and decreased ATP production might be important pathological mechanisms in T1DC formation, whereas crystallin modification and cross-linking/aggregation as well as IF degradation may play more crucial roles in T2DC formation.

Use of a silk fibroin-chitosan scaffold to construct a tissue-engineered corneal stroma.

PURPOSE: To construct a scaffold using silk fibroin (SF) and chitosan (CS) that could replace the corneal stroma with the biological characteristics of the scaffold materials still intact. METHODS: To develop an organotypic corneal stroma, SF and CS were chosen to synthesise the tissue-engineered bioscaffold. We cultured primary rabbit corneal epithelial cells and corneal stromal cells in vitro. Keratocytes were used to assess cytotoxicity on SF-CS (SFCS) blends, which was determined by a Cell Counting Kit-8 assay. The corneal lamellar scaffolds were developed with sequential culture techniques to form cell-scaffold constructs. Implantation was tested in 15 New Zealand White rabbits. The corneal substitutes were analysed by light and electron microscopy. RESULTS: The reconstructed lamellar cornea was comparable to native tissue, with high levels of K3/12 expression in the corneal epithelial cells and vimentin in the stromal cells; moreover, the morphology and the position of the cells could be distinguished by histological methods. There was no sign of any immune reaction in or around the transplanted discs 12 weeks after implantation. CONCLUSION: A SFCS scaffold might be a suitable blend for corneal tissue engineering.

Leukocytes from diabetic patients kill retinal endothelial cells: effects of berberine.

PURPOSE: Accumulating evidence in animals suggests that leukocytes are involved in the pathogenesis of diabetic retinopathy. The present study was designed to investigate whether leukocytes from diabetic patients could kill retinal endothelial cells and whether that cytotoxicity could be inhibited in vivo by administration of berberine. METHODS: Human retinal endothelial cells (HRECs) were cocultured (24 h) with leukocytes freshly isolated from nondiabetic and diabetic patients, and leukocyte-mediated death of HRECs was analyzed with flow cytometry. HRECs or leukocytes were incubated with antibodies against intercellular adhesion molecule-1(ICAM-1) or integrin beta-2, or with various concentrations of berberine. The protein expression levels of inflammatory factors were investigated using western blots, and activities of antioxidant enzymes and malondialdehyde content were examined as markers of oxidative stress. In addition, leukocytes were isolated from 28 diabetic patients with retinopathy and nondiabetic patients before and after 1 month in vivo therapy with berberine. The effects of the berberine on leukocyte-mediated killing of endothelial cells was again assessed. RESULTS: Leukocytes from diabetic patients induced more apoptosis of HRECs in a coculture system than did cells from nondiabetic patients, and this killing occurred primarily via direct cell-cell contact. Berberine inhibited the leukocyte-mediated killing of HRECs in vitro, the decrease in antioxidant enzyme activities, the nuclear translocation of nuclear factor kappa B, and the increase in intercellular adhesion molecule-1 and inducible nitric oxide synthase expression and malondialdehyde content in HRECs cultured in high glucose. Berberine also decreased integrin beta-2 expression of leukocytes in vitro and in vivo. Oral consumption of berberine for 1 month likewise inhibited the diabetes-induced increase in leukocyte-mediated killing of HRECs. CONCLUSIONS: Our findings suggest that leukocytes from diabetic patients kill retinal endothelial cells, and that berberine can inhibit this leukocyte-mediated killing of vascular endothelium. Coculture of leukocytes with HRECs might serve as a biomarker to study the role of leukocytes in the development of diabetic retinopathy, and the data are consistent with berberine being a therapy against diabetic retinopathy.

Chitosan-functionalized silk fibroin 3D scaffold for keratocyte culture.

The goal of this study was to evaluate the potential suitability of an artificial membrane composed of silk fibroin (SF) functionalized by different ratios of chitosan (CS) as a substrate for the stroma of the cornea. Keratocytes were cultured on translucent membranes made of SF and CS with different ratios. The biophysical properties of the silk fibroin and chitosan (SF/CS) membrane were examined. The SF/CS showed tensile strengths that increased as the CS concentration increased, but the physical and mechanical properties of chitosan-functionalized silk fibroin scaffolds weakened significantly compared with those of native corneas. The resulting cell scaffolds were evaluated using western blot in addition to light and electron microscopy. The cell attachment and proliferation on the scaffold were similar to those on a plastic plate. Keratocytes cultured in serum on SF/CS exhibited stellate morphology along with a marked increase in the expression of keratocan compared with identical cultures on tissue culture plastics. The biocompatibility was tested by transplanting the acellular membrane into rabbit corneal stromal pockets. There was no inflammatory complication detected at any time point on the macroscopic level. Taken together, these results indicate that SF/CS holds promise as a substrate for corneal reconstruction.

A C-terminal fragment BIGH3 protein with an RGDRGD motif inhibits corneal neovascularization in vitro and in vivo.

An Arg-Gly-Asp (RGD) motif in the fourth FAS1 domain of the human BIGH3 (transforming growth factor-ß1-inducible gene-h3) protein has been reported to play an important role in mediating tumor angiogenesis. The aim of this study was to investigate the inhibitory effect of a modified C-terminal fragment BIGH3 protein with an RGDRGD motif on corneal neovascularization in vitro and in vivo. Recombinant C-terminal fragment BIGH3 protein with wild-type sequence and modified C-terminal fragment BIGH3 protein containing an RGDRGD motif were successfully expressed and purified. We demonstrated that both proteins significantly inhibited vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) adhesion, migration, and tube formation and induced cell apoptosis but failed to inhibit HUVEC proliferation. We determined that the mechanism underlying this activity was an interaction between BIGH3 and αvß3 integrin, which blocked the phosphorylation of PI3K/Akt and ERK signaling pathways. The inhibitory effects of wild-type and modified C-terminal fragment BIGH3 proteins on angiogenesis were confirmed by a rabbit corneal neovascularization assay. More importantly, we provided evidence that the modified C-terminal fragment BIGH3 protein with an RGDRGD motif inhibited angiogenic activity far more effectively than did wild-type C-terminal fragment BIGH3. Collectively, our data show that a C-terminal fragment BIGH3 protein containing an RGDRGD motif might be promising as an effective drug in treating corneal neovascularization.

A novel mutation in GJA3 associated with congenital Coppock-like cataract in a large Chinese family.

PURPOSE: To identify the potential pathogenic mutation over five generations of a Chinese family with congenital Coppock-like cataracts (CCL). METHODS: We investigated five generations of a Chinese family affected with CCL. The family resides in a relatively isolated region of northern China. Peripheral blood samples were collected from all of the family members, and genomic DNA was then extracted from the blood samples. A genome-wide linkage scan was performed using about 400 microsatellite markers. Two-point LOD (linkage odd disequilibrium) scores (Z) were calculated using the LINKAGE programs (ver. 5.1). Cyrillic software processed the resulting haplotypes. Mutation detection was performed in the candidate gene by direct sequencing. RESULTS: The maximum LOD score was obtained at marker D13S175 (lod score [Z(max)]=5.90; recombination fraction [θ]=0.0). Haplotype analysis traced the disease gene to a 6.99-cM interval bounded by D13S1316 and D13S1275 on chromosome 13q12.11. Direct sequencing of the candidate gene GJA3 (gap junction protein alpha-3) revealed a c.427G>A transition in exon 2 of GJA3 that co-segregated with the cataract in the family members and was not observed in 100 control patients. This single-nucleotide change resulted in the substitution of a highly conserved glycine by arginine (G143R). CONCLUSIONS: The present study identified a novel mutation in GJA3 that causes CCL. As the first report to relate p.G143R mutation in GJA3, it expands the mutation spectrum of GJA3. Our report is the first in identification of the mutation of GJA3 in the cytoplasmic-loop domain. This mutation is associated with multiple members of a five-generation family with congenital CCL.

A comparison of the effectiveness between amniotic membrane homogenate and transplanted amniotic membrane in healing corneal damage in a rabbit model.

PURPOSE: To determine whether amniotic membrane homogenate is as effective in healing corneal damage as amniotic membrane transplantation in a rabbit model. METHOD: The rabbits were divided into three groups. The cornea of one eye in each rabbit was incised resulting in a defect of approximately 8 mm in diameter. Amniotic membrane transplantation was performed in the first group, and amnion homogenate was administered four times a day in the second group. The third group was the control group. RESULTS: There were no differences in the diameter of the defects and the rate of corneal growth between the amnion transplant group and the amnion homogenate group. CONCLUSION: Amnion homogenate is as effective as transplanted amniotic membrane in promoting corneal healing in a rabbit model.