Junction Barrier Research Articles

β-arrestin1 protects intestinal tight junction through promoting mitofusin 2 transcription to drive parkin-dependent mitophagy in colitis.

Intestinal barrier defect is an essential inflammatory bowel disease (IBD) pathogenesis. Mitochondrial dysfunction results in energy deficiency and oxidative stress, which contribute to the pathogenesis of IBD. β-arrestin1 (ARRB1) is a negative regulator that promotes G protein-coupled receptors desensitization, endocytosis, and degradation. However, its role in maintaining the intestinal barrier remains unclear. Dextran sulfate sodium-induced colitis was performed in ARRB1 knockout and wild-type mice. Intestinal permeability and tight junction proteins were measured to evaluate the intestinal barrier. Mitochondria function and mitophagic flux in mice and cell lines were detected. Finally, the interaction between ARRB1 and mitofusin 2 was investigated by co-immunoprecipitation and dual luciferase assay. We identified that ARRB1 protected the intestinal tight junction barrier against experimental colitis in vivo. ARRB1 deficiency was accompanied by abnormal mitochondrial morphology, lower adenosine triphosphate (ATP) production, and severe oxidative stress. In vitro, the knockdown of ARRB1 reduced ATP levels and mitochondrial membrane potential while increasing reactive oxygen species levels and oxidative stress. Upon ARRB1 ablation, mitophagy was inhibited, accompanied by decreased LC3BII, phosphatase and tension homologue-induced protein kinase1 (PINK1), and parkin, but increased p62 expression. Mitophagy inhibition via PINK1 siRNA or mitochondrial division inhibitor 1 impaired ARRB1-mediated tight junction protection. The interaction of ARRB1 with E2F1 activated mitophagy by enhancing the transcription of mitofusin 2. Our results suggest that ARRB1 is critical to maintaining the intestinal tight junction barrier by promoting mitophagy. These results reveal a novel link between ARRB1 and the intestinal tight junction barrier, which provides theoretical support for colitis treatment.

(Invited) Towards GaN-on-GaN High-Power Electronic Devices

Application of gallium nitride (GaN) substrates in electronic and optoelectronic industries is constantly increasing. In order to fabricate wafers, GaN crystals of the highest structural quality and desired electrical (and sometimes optical) properties must be grown. Today, there are three main GaN crystallization methods: i/ halide vapor phase epitaxy (HVPE) with its derivatives: halide-free VPE and oxide VPE; ii/ sodium-flux; and iii/ ammonothermal. The last approach can be basic or acidic depending on what mineralizer is used to increase the solubility of GaN in the feedstock zone. In this paper we will focus on HVPE and basic ammonothermal growth of GaN [1]. Not only bulk growth will be presented. The HVPE method will also be discussed as the best method to crystallize the drift layers necessary for high-power vertical electronic devices (FET transistors, Schottky diodes).One of the best methods for introducing dopants into semiconductors is ion implantation. The introduced structural damage can be removed by a proper annealing process. The high-temperature treatment enables also electrical and/or optical activation of the implanted dopants. In the case of GaN, annealing at high temperature (~1300°C - 1400°C) seems difficult. This compound loses its thermodynamic stability slightly above 800°C at atmospheric pressure. At higher temperature the crystal will decompose. One of the solutions is to anneal GaN at high nitrogen (N2) pressure. Such technology is called ultra-high-pressure annealing (UHPA) [2]. In this paper, application of UHPA for GaN crystals and layers implanted by different ions (acceptors and donors) will be presented. The latest results of the implantation with magnesium (Mg), beryllium (Be), zinc (Zn), and calcium (Ca) ions into GaN in order to obtain p-type conductivity will be discussed [3,4]. Silicon (Si) implantation into GaN for n-type doping will also be analyzed. Structural, electrical and optical properties of implanted GaN after UHPA will be discussed in terms of application for GaN-based devices.A kV class, low ON-resistance, vertical GaN junction barrier Schottky (JBS) diode with selective-area p-regions formed via Mg implantation followed by high-temperature, ultra-high pressure post-implantation activation anneal without a capping layer was already demonstrated [5]. The forward characteristics of the JBS diode showed ideality factor (n) 1.03, turn-on voltage (VON) 0.75 V, current ON/OFF ratio (at ±3 V) ~1011, and specific differential ON-resistance (RON) 0.6 mΩ·cm2. The breakdown voltage of the JBS diode was 915 V.

(Invited) Role of Heterojunctions in Metal Oxide Heterostructures for Energy and Environmental Applications

Heterostructures made from metal oxide semiconductors are fundamental for the development of high-performance gas sensors and electrocatalysts, for examples. Here, I will introduce hierarchical heterostructures composed of p-, n-type and insulating metal oxide shells.Precisely controlled films of alternating metal oxides can be uniformly deposited onto the inner and outer walls of the CNTs and onto mesoporous substrates by atomic layer deposition. The morphological, microstructural and electrical characteristics of the heterostructures were thoroughly investigated. Electrical resistance measurements highlighted the large influence of the metal oxides thickness and charge carriers types, suggesting that the conductivity of the electrodes are dominated by Schottky barrier junctions across the heterojunctions.The behavior of the heterostructured electrodes in sensors and in electrocatalysis applications was investigated for low concentrations of volatile organic compounds and pollutants, and the oxygen evolution reaction in acidic media, respectively. For examples, the gas sensing response of the heterostructures showed a strong dependence on the thickness of the metal oxide shell layers and the type of heterostructures formed. On the other hand, the electrocatalytic performances are strongly related to the surface catalyst/stabilization layer and the electrical conductivity of the heterostructured electrode.On the basis of the morphological, microstructural and electrical characterization, and electrode performances, the mechanisms which account for the performances of our heterostructured electrodes will be correlated and discussed.

Novel digital terahertz device for three-state logic gate and phase coding based on graphene and Schottky barrier junctions

Terahertz technology, III-V group semiconductor devices, and graphene have great potential for broad applications in 6 G wireless communications. A novel digital terahertz device with nickel/GaN and graphene/GaN Schottky barrier junctions was proposed in this study. The patterned metal electrodes of the device, together with the graphene layer, formed a terahertz metasurface. The mechanisms of modulating the fermi level of graphene and the conductivity of the device to manipulate the transmission coefficient and reflected phase of terahertz waves were investigated using numerical calculations. The electrical and optical simulation results theoretically demonstrated that the three-state logic gate operation for the transmission coefficient of terahertz wave at 1.458 THz and the 1-bit reflected phase coding manipulation in 1.51–1.55 THz were realized. In addition, the maximum radar cross section reduction for the reflected wave was approximately 11.14 dB, comparing the designed coding sequences with the metal plate. These functions are mainly implemented by applying an external bias voltage to the device. This study provides a new and feasible strategy for designing digital terahertz manipulation devices.

An Ultrahigh‐Rectification‐Ratio WSe2 Homojunction Defined by High‐Efficiency Charge Trapping Effect

AbstractAlthough 2D material van der Waals heterostructures (vdWHs) exhibit many novel properties and applications, 2D homojunctions have unique advantages in interface lattice matching, band continuity, and charge transfer efficiency. However, the rectification performances of 2D homojunction diodes are severely limited by the small junction barrier, mainly due to inefficient charge doping. In this work, an ultrahigh‐rectification‐ratio WSe2 homojunction diode achieved by the semi‐floating gate doping of graphdiyne oxide (GDYO) is reported. Utilizing the WSe2/GDYO direct charge trapping mode can free the inhibition of charge capturing efficiency by removing conventional insulating barriers and thus improve the rectification ratio. The C─C(sp) and oxygen‐containing functional groups in the GDYO layer can provide outstanding charge‐trapping ability due to their unsaturation. Furthermore, the oxygen plasma treatment used for oxidizing graphdiyne (GDY) into GDYO can make GDYO a flatter surface, thus creating strong‐coupling WSe2/GDYO interfaces to improve the charge transfer efficiency and enhance the electrostatic doping effect. Besides, the WSe2/GDYO interfaces are confirmed to possess a higher junction barrier than that of the WSe2/GDY interfaces. This research proposes a brand‐new approach to building p–n junctions via charge trapping and the homojunction diode with a record‐highest rectification ratio of up to 106 is obtained.

O-GlcNAcylation Inhibition Upregulates Connexin43 Expression in the Endothelium to Protect the Tight Junction Barrier in Diabetic Retinopathy.

This study aimed to investigate the effects of O-linked N-acetylglucosamine modification (O-GlcNAcylation) on connexin43 (Cx43) expression and its subsequent effects on tight junction properties in diabetic retinopathy (DR). O-GlcNAcylation levels in primary human retinal vascular endothelial cells (HRVECs) and retinas from rats with diabetes were regulated by treatment with Thiamet G or alloxan. Immunoprecipitation was used to examine the relationship between O-GlcNAcylation and Cx43 expression. Stable overexpression and knockdown of Cx43 in HRVECs were achieved using lentivirus constructs; further, their effects on occludin and zonula occluden-1 (ZO-1) expression and tight junction barrier function were determined. O-GlcNAcylation level increased significantly, whereas Cx43 expression decreased in retinas from rats with diabetes and HRVECs cultured under high-glucose conditions. Immunoprecipitation revealed that Cx43 was modified by O-GlcNAcylation and phosphorylation simultaneously. O-GlcNAcylation inhibition negatively regulated both total Cx43 and phosphorylated Cx43 expression, subsequently disrupting tight junction properties. Conversely, Cx43 overexpression reversed the disruption of tight junction properties and downregulated vascular endothelial growth factor expression. Consistently, Cx43 overexpression increased transendothelial electrical resistance values in HRVEC layers. O-GlcNAcylation negatively regulated Cx43 expression, contributing to the disruption of the blood retinal barrier. However, O-GlcNAcylation inhibition and Cx43 overexpression could reverse the tight junction disruption. Therefore, O-GlcNAcylation inhibition is a potential target for avoiding tight junction disruption through the Cx43 pathway in DR.

The traditional herb Sargentodoxa cuneata alleviates DSS-induced colitis by attenuating epithelial barrier damage via blocking necroptotic signaling

Ethnopharmacological relevanceThe traditional Chinese herb, Sargentodoxa cuneata, is primarily utilized as a crucial herb for managing ulcerative colitis (UC), also known as “Da Xue Teng (DXT)” or “Hong Teng” in Chinese. Nevertheless, the chemical composition, prototype, and metabolite constituents of DXT and its pharmacological mechanism of treatment for UC remain unclear. Aim of the studyNecroptosis, a caspase-independent form of programmed cell death, plays a crucial role in the inflammatory pathogenesis of UC. The occurrence of necroptosis in intestinal epithelial cells triggers a robust inflammatory response and disrupts the integrity of both the mucinous barrier and tight junction construction. The objective of our study was to determine the chemical composition of DXT, identify its absorbed active ingredients and metabolites in rat serum, and investigate whether DXT possesses epithelial barrier protective effects by inhibiting necroptosis. Materials and methodsFirst, the UPLC-Q-TOF/MS was applied to identify the chemical composition of DXT, as well as the absorption components and metabolites of DXT in rat serum. Second, the network pharmacology analysis was further investigated to elucidate the potential targets for treating UC. Finally, the mechanism of action was validated by necroptosis-based experiment in vitro and an in vivo model of colitis. ResultsA comprehensive analysis revealed the presence of 31 phytochemicals derived from DXT herb, as well as a total of 39 components in rat serum. Network pharmacology analysis indicated that TNF, EGFR, HSP90, etc. are the potential targets. Experimental in vitro and in vivo verified that the DXT could improve disease activity index, body weight, colon length and intestinal barrier permeability in mice with colitis by inhibiting necroptosis of intestinal epithelial cells. ConclusionsIn this study, the phytochemicals derived from DXT herb and absorption active ingredients and metabolites of DXT in rat serum were analyzed. The biological mechanism of treatment for UC can be elucidated by combining network pharmacology investigation with experimental in vitro and in vivo studies. The findings offered a theoretical basis for comprehending the bioactive substances and the pharmacological process of DXT.

Tunable p–n junction barriers in few-electron bilayer graphene quantum dots

Graphene quantum dots provide promising platforms for hosting spin, valley, or spin-valley qubits. Taking advantage of their electrically generated bandgap and their ambipolar nature, high-quality quantum dots can be defined in bilayer graphene using natural p–n junctions as tunnel barriers. In these devices, demonstrating the electrical tunability of the p–n junction barriers and understanding its physical mechanism, especially in the few-electron regime, are essential for further manipulating electrons' quantum degrees of freedom to encode qubits. Here, we show the electrostatic confinement of single quantum dots in bilayer graphene using natural p–n junctions. When the device is operated in the few-electron regime, the electron tunneling rate is found to be monotonically tuned by varying gate voltages, which can be well understood from the view of manipulating the p–n junction barriers. Our results provide an insightful understanding of electrostatic confinement using natural p–n junctions in bilayer graphene, which is beneficial for realizing graphene-based qubits.

Genotoxicity of bisphenol AF in rats: Detrimental to male reproductive system and probable stronger micronucleus induction potency than BPA.

Bisphenol AF (BPAF), as one of structural analogs of BPA, has been increasingly used in recent years. However, limited studies have suggested its adverse effects similar to or higher than BPA. In order to explore the general toxicity and genotoxicity of subacute exposure to BPAF, the novel 28-day multi-endpoint (Pig-a assay + micronucleus [MN] test + comet assay) genotoxicity evaluation platform was applied. Male rats were randomly distributed into seven main experimental groups and four satellite groups. The main experimental groups included BPAF-treated groups (0.5, 5, and 50 μg/kg·bw/d), BPA group (10μg/kg·bw/d), two solvent control groups (PBS and 0.1% ethanol/99.9% oil), and one positive control group (N-ethyl-N-nitrosourea, 40 mg/kg bw). The satellite groups included BPAF high-dose recovery group (BPAF-HR), oil recovery group (oil-R), ENU recovery group (ENU-R), and PBS recovery group (PBS-R). All groups received the agents orally via gavage for 28 consecutive days, and satellite groups were given a recovery period of 35 days. Among all histopathologically examined organs, testis and epididymis damage was noticed, which was further manifested as blood-testis barrier (BTB) junction protein (Connexin 43 and Occludin) destruction. BPAF can induce micronucleus production and DNA damage, but the genotoxic injury can be repaired after the recovery period. The expression of DNA repair gene OGG1 was downregulated by BPAF. To summarize, under the design of this experiment, male reproductive toxicity of BPAF was noticed, which is similar to that of BPA, but its ability to induce micronucleus production may be stronger than that of BPA.

Teriflunomide Promotes Blood-Brain Barrier Integrity by Upregulating Claudin-1 via the Wnt/β-catenin Signaling Pathway in Multiple Sclerosis.

The blood-brain barrier (BBB) and tight junction (TJ) proteins maintain the homeostasis of the central nervous system (CNS). The dysfunction of BBB allows peripheral T cells infiltration into CNS and contributes to the pathophysiology of multiple sclerosis (MS). Teriflunomide is an approved drug for the treatment of MS by suppressing lymphocytes proliferation. However, whether teriflunomide has a protective effect on BBB in MS is not understood. We found that teriflunomide restored the injured BBB in the EAE model. Furthermore, teriflunomide treatment over 6months improved BBB permeability and reduced peripheral leakage of CNS proteins in MS patients. Teriflunomide increased human brain microvascular endothelial cell (HBMEC) viability and promoted BBB integrity in an in vitro cell model. The TJ protein claudin-1 was upregulated by teriflunomide and responsible for the protective effect on BBB. Furthermore, RNA sequencing revealed that the Wnt signaling pathway was affected by teriflunomide. The activation of Wnt signaling pathway increased claudin-1 expression and reduced BBB damage in cell model and EAE rats. Our study demonstrated that teriflunomide upregulated the expression of the tight junction protein claudin-1 in endothelial cells and promoted the integrity of BBB through Wnt signaling pathway.

Correlations between reverse bias leakage current, cathodoluminescence intensity and carbon vacancy observed in 4H-SiC junction barrier Schottky diode

Reverse bias currents of ten commercial junction barrier Schottky diodes were measured, and the dies were studied by scanning electron microscope (SEM) and cathodoluminescence (CL) after the de-capsulation of the diodes. Defect emissions (DEs) of 2.62 eV were observed in all the CL spectra. By comparing the SEM images, the integral CL intensity spatial mappings and the reverse bias leakage currents, correlations between the leakage current, the integral CL intensity and the Al-implantation process were established. The data of reverse bias leakage current against the reverse bias voltage taken at room temperature followed the Poole Frenkel emission from the Z 1/Z 2 carbon vacancy states to the conduction band. The DE at 2.62 eV is associated with the electronic transition from Z 1/Z 2 to the valence band. The current observation also opens up the feasibility of screening off SiC diodes with large leakage current during production by inspecting the CL intensity before the device fabrication is complete.

C-TYPE LECTIN-2D RECEPTOR CONTRIBUTES TO HISTONE-INDUCED VASCULAR BARRIER DYSFUNCTION DURING BURN INJURY.

Severe burns are associated with massive tissue destruction and cell death where nucleus histones and other damage-associated molecular patterns are released into the circulation and contribute to the pathogenesis of multiple-organ dysfunction. Currently, there is limited information regarding the pathophysiology of extracellular histones after burns, and the mechanisms underlying histone-induced vascular injury are not fully understood. In this study, by comparing the blood samples from healthy donors and burn patients, we confirmed that burn injury promoted the release of extracellular histones into the circulation, evidenced by increased plasma levels of histones correlating with injury severity. The direct effects of extracellular histones on human endothelial monolayers were examined, and the results showed that histones caused cell-cell adherens junction discontinuity and barrier dysfunction in a dose-related manner. Like burn patients, mice subjected to a scald burn covering 25% total body surface area also displayed significantly increased plasma histones. Intravital microscopic analysis of mouse mesenteric microcirculation indicated that treatment with a histone antibody greatly attenuated burn-induced plasma leakage in postcapillary venules, supporting the pathogenic role of extracellular histones in the development of microvascular barrier dysfunction during burns. At the molecular level, intrigued by the recent discovery of C-type lectin domain family 2 member D (Clec2d) as a novel receptor of histones, we tested its potential involvement in the histone interaction with endothelial cells. Indeed, we identified abundant expression of Clec2d in vascular endothelial cells. Further proximity ligation assay demonstrated a close association between extracellular histones and endothelial expressing Clec2d. Functionally, in vivo administration of an anti-Clec2d antibody attenuated burn-induced plasma leakage across mesenteric microvessels. Consistently, Clec2d knockdown in endothelial cells partially inhibited histone-induced endothelial barrier dysfunction. Together, our data suggest that burn injury-induced increases in circulating histones contribute to microvascular leakage and endothelial barrier dysfunction via a mechanism involving the endothelial Clec2d receptor.

The functional switching on the operating modes of a piezoelectric semiconductor bipolar junction transistor via mechanical loadings

A nonlinear model was developed on piezoelectric bipolar junction transistors (PS-BJTs) subjected to mechanical loadings by disregarding the assumption of low injection and the approximation of depletion layer. It was found that a PS-BJT subjected to different mechanical loadings can exhibit distinct carrier flow directions, for example, a remarkable transition for an n+pn-type PS-BJT from a transistor unit with amplification capability to two parallel connected PN junctions by applying a pair of lateral tensile or compressive stresses at the emitter and collector interfaces. Further in-depth analysis revealed that shielding effect produced by base region carriers greatly varies according to different loading mode, which leads to changing degrees of mechanical reconstruction on emitter junction barrier. Consequently, an artificial electron pathway (AEP) is formed at the emitter junction by a specific loading configuration. It is just due to the form change of AEP to produce distinct carrier flow directions, which can realize multifunctional switching of electronic devices. In addition, we also found an interesting phenomenon that an AEP can be directly constructed to penetrate the emitter junction by applying mechanical loadings in the longitudinal direction such that electrons in emitter region can travel across the emitter interface directly to the collector region without regulated by the base current. Under that situation, the PS-BJT resembles a parallel combination of a PN junction and an NN junction. This research provides novel insights into the mechanical modulation of piezoelectric electronic devices and the design of novel logic circuits.

Effect of substrate thinning on heavy ion induced single event effect in silicon carbide power junction barrier Schottky diodes

Experimental responses of two different substrate thicknesses of SiC Junction-Barrier-Schottky (JBS) diodes are presented by Kr and Bi ions irradiation experiments. Three bias voltages of 250 V, 275 V, and 300 V were chosen to analyse single event leakage current (SELC) degradation and single event burnout (SEB) in the 650 V-rated devices with standard (350 μm) and thin (150 μm) substrates, respectively. Measured data indicate that under the same bias voltage and heavy ion parameter conditions, the degree of leakage degradation of the device is weaker for the SiC JBS with thin substrate structure. Measured data also indicate that when the device at a bias voltage of 300 V by the Bi-ion irradiation experiment, SEB occurred in the standard substrate device, but only leakage current degradation occurred in the thin substrate device. The weakening of effective charge deposition and impact ionization rate in thin-substrate devices are the main reasons for SELC degradation and SEB threshold increasing. Corresponding TCAD simulations are also utilized to analyse physical parameters and confirm the mechanism.

Toxic effects of combined exposure to cadmium and nitrate on intestinal morphology, immune response, and microbiota in juvenile Japanese flounder (Paralichthys olivaceus)

Cadmium (Cd2+) and nitrate (NO3−) are important environmental pollutants in the offshore marine ecological environment. However, limited research has explored their combined effects, particularly regarding their impact on the microbiota and intestinal health of marine fish. In this study, juvenile Japanese flounders (P. olivaceus) were immersed in seawater samples with different combinations of Cd2+ (0, 0.2, and 2 mg/L) and NO3− (0 and 80 mg/L NO3N) for 30 days to explore their toxic impacts on intestinal morphology, tight junction (TJ) barrier, immune response, and microbiota. Our results showed that Cd2+ or NO3− exposure alone led to histopathological damage of the gut, while their co-exposure aggravated intestinal damage. Moreover, co-exposure substantially decreased TJ-related gene expression, including occludin, claudin-10, and ZO-2, suggesting increased TJ permeability in the gut. Regarding the immune response, we observed upregulated expression of immune-related markers such as HSP40, IL-1β, TNF-α, and MT, suggesting the onset of intestinal inflammation. Furthermore, Cd2+ and NO3– exposure led to changes in intestinal microflora, characterized by decreased the abundance of Sediminibacterium and NS3a_marine_group while increasing the prevalence of pathogens or opportunistic pathogens such as Ralstonia, Proteus, and Staphylococcus. This alteration in microbiota composition increased network complexity and α-diversity, ultimately causing dysbiosis in the fish gut. Additionally, combined exposure resulted in metabolic disorders that affected the predicted functions of the intestinal microbiota. Overall, our study demonstrates that Cd2+–NO3– co-exposure amplifies the deleterious effects compared to single exposure. These findings enhance our understanding of the ecological risks posed by Cd2+–NO3– co-exposure in marine ecosystems.

Critical contributions of protein cargos to the functions of macrophage-derived extracellular vesicles

BackgroundMacrophages are highly plastic innate immune cells that play key roles in host defense, tissue repair, and homeostasis maintenance. In response to divergent stimuli, macrophages rapidly alter their functions and manifest a wide polarization spectrum with two extremes: M1 or classical activation and M2 or alternative activation. Extracellular vesicles (EVs) secreted from differentially activated macrophages have been shown to have diverse functions, which are primarily attributed to their microRNA cargos. The role of protein cargos in these EVs remains largely unexplored. Therefore, in this study, we focused on the protein cargos in macrophage-derived EVs.ResultsNaïve murine bone marrow-derived macrophages were treated with lipopolysaccharide or interlukin-4 to induce M1 or M2 macrophages, respectively. The proteins of EVs and their parental macrophages were subjected to quantitative proteomics analyses, followed by bioinformatic analyses. The enriched proteins of M1-EVs were involved in proinflammatory pathways and those of M2-EVs were associated with immunomodulation and tissue remodeling. The signature proteins of EVs shared a limited subset of the proteins of their respective progenitor macrophages, but they covered many of the typical pathways and functions of their parental cells, suggesting their respective M1-like and M2-like phenotypes and functions. Experimental examination validated that protein cargos in M1- or M2-EVs induced M1 or M2 polarization, respectively. More importantly, proteins in M1-EVs promoted viability, proliferation, and activation of T lymphocytes, whereas proteins in M2-EVs potently protected the tight junction structure and barrier integrity of epithelial cells from disruption. Intravenous administration of M2-EVs in colitis mice led to their accumulation in the colon, alleviation of colonic inflammation, promotion of M2 macrophage polarization, and improvement of gut barrier functions. Protein cargos in M2-EVs played a key role in their protective function in colitis.ConclusionThis study has yielded a comprehensive unbiased dataset of protein cargos in macrophage-derived EVs, provided a systemic view of their potential functions, and highlighted the important engagement of protein cargos in the pathophysiological functions of these EVs.

COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), could affect brain structure and function. SARS-CoV-2 can enter the brain through different routes, including the olfactory, trigeminal, and vagus nerves, and through blood and immunocytes. SARS-CoV-2 may also enter the brain from the peripheral blood through a disrupted blood-brain barrier (BBB). The neurovascular unit in the brain, composed of neurons, astrocytes, endothelial cells, and pericytes, protects brain parenchyma by regulating the entry of substances from the blood. The endothelial cells, pericytes, and astrocytes highly express angiotensin converting enzyme 2 (ACE2), indicating that the BBB can be disturbed by SARS-CoV-2 and lead to derangements of tight junction and adherens junction proteins. This leads to increased BBB permeability, leakage of blood components, and movement of immune cells into the brain parenchyma. SARS-CoV-2 may also cross microvascular endothelial cells through an ACE2 receptor–associated pathway. The exact mechanism of BBB dysregulation in COVID-19/neuro-COVID is not clearly known, nor is the development of long COVID. Various blood biomarkers could indicate disease severity and neurologic complications in COVID-19 and help objectively diagnose those developing long COVID. This review highlights the importance of neurovascular and BBB disruption, as well as some potentially useful biomarkers in COVID-19, and long COVID/neuro-COVID.

Activation of the 5-hydroxytryptamine 4 receptor ameliorates tight junction barrier dysfunction in the colon of type 1 diabetic mice.

Hyperglycemia drives dysfunction of the intestinal barrier. 5-Hydroxytryptaine 4 receptor (5-HT 4R) agonists have been considered therapeutics for constipation in clnic. However, the roles of 5-HT 4R activation in mucosa should be fully realized. Here, we investigate the effects of 5-HT 4R activation on diabetes-induced disruption of the tight junction (TJ) barrier in the colon. Not surprisingly, the TJ barrier in diabetic mice with or without 5-HT 4R is tremendously destroyed, as indicated by increased serum fluorescein isothiocyanate (FITC)-dextran and decreased transepithelial electrical resistance (TER). Simultaneously, decreased expressions of TJ proteins are shown in both wild-type (WT) and 5-HT 4R knockout (KO) mice with diabetes. Notably, chronic treatment with intraperitoneal injection of a 5-HT 4R agonist in WT mice with diabetes repairs the TJ barrier and promotes TJ protein expressions, including occludin, claudin-1 and ZO-1, in the colon, whereas a 5-HT 4R agonist does not improve TJ barrier function or TJ protein expressions in 5-HT 4R KO mice with diabetes. Furthermore, stimulation of 5-HT 4R inhibits diabetes-induced upregulation of myosin light chain kinase (MLCK), Rho-associated coiled coil protein kinase 1 (ROCK1), and phosphorylated myosin light chain (p-MLC), which are key molecules that regulate TJ integrity, in the colonic mucosa of WT mice. However, such action induced by a 5-HT 4R agonist is not observed in 5-HT 4R KO mice with diabetes. These findings indicate that 5-HT 4R activation may restore TJ integrity by inhibiting the expressions of MLCK, ROCK1 and p-MLC, improving epithelial barrier function in diabetes.

Effects of functional nutrients on chicken intestinal epithelial cells induced with oxidative stress.

The objective of this study was to investigate the protective effects of functional nutrients including various functional amino acids, vitamins, and minerals on chicken intestinal epithelial cells (cIECs) treated with oxidative stress. The cIECs were isolated from specific pathogen free eggs. Cells were exposed to 0 mM supplement (control), 20 mM threonine (Thr), 0.4 mM tryptophan (Trp), 1 mM glycine (Gly), 10 μM vitamin C (VC), 40 μM vitamin E (VE), 5 μM vitamin A (VA), 34 μM chromium (Cr), 0.42 μM selenium (Se), and 50 μM zinc (Zn) for 24 h with 6 replicates for each treatment. After 24 h, cells were further incubated with fresh culture medium (positive control, PC) or 1 mM H2O2 with different supplements (negative control, NC and each treatment). Oxidative stress was measured by cell proliferation, whereas tight junction barrier function was analyzed by fluorescein isothiocyanate (FITC)-dextran permeability and transepithelial electrical resistance (TEER). Results indicated that cell viability and TEER values were less (p < 0.05) in NC treatments with oxidative stress than in PC treatments. In addition, FITC-dextran values were greater (p < 0.05) in NC treatments with oxidative stress than in PC treatments. The supplementations of Thr, Trp, Gly, VC, and VE in cells treated with H2O2 showed greater (p < 0.05) cell viability than the supplementation of VA, Cr, Se, and Zn. The supplementations of Trp, Gly, VC, and Se in cells treated with H2O2 showed the least (p < 0.05) cellular permeability. In addition, the supplementation of Thr, VE, VA, Cr, and Zn in cells treated with H2O2 decreased (p < 0.05) cellular permeability. At 48 h, the supplementations of Thr, Trp, and Gly in cells treated with H2O2 showed the greatest (p < 0.05) TEER values among all treatments, and the supplementations of VC and VE in cells treated with H2O2 showed greater (p < 0.05) TEER values than the supplementations of VA, Cr, Se, and Zn in cells treated with H2O2. In conclusion, Thr, Trp, Gly, and VC supplements were effective in improving cell viability and intestinal barrier function of cIECs exposed to oxidative stress.

Effect of Total Dose Irradiation on Parasitic BJT in 130 nm PDSOI MOSFETs.

In this work, the effects of total dose irradiation on the parasitic bipolar junction transistor (BTJ) in 130 nm PDSOI MOSFETs were investigated. The experimental results demonstrate that irradiation-induced oxide-trap charges can modify the E-B junction barrier, and thereby make the common-emitter gain β0 of the parasitic BJT in NMOS device increase, while decreasing it in a PMOS device. Additionally, irradiation-generated oxide-trap charges in shallow trench isolation (STI) elevate the surface electrostatic potential of the gate above the STI sidewall, thus providing an additional channel from the emitter to the collector. Moreover, these charges may generate parasitic reverse conductive paths at the STI/Si interface under high dose irradiation, thereby enhancing the leakage current in the front gate channel and diminishing the significance of the parasitic BJT. Under irradiation, the electric field intensity difference between two biases leads to higher β0 of the parasitic BJT in PG-biased devices than in ON-biased ones. Furthermore, the lifting effect of irradiation on β0 increases in wide or short channel irradiated devices, which can be explained using simulations and an emitter current crowding effect model.