Junction Degradation Research Articles

Astrocytic p75NTR expression provoked by ischemic stroke exacerbates the blood-brain barrier disruption.

The disruption of the blood-brain barrier (BBB) plays a critical role in the pathology of ischemic stroke. p75 neurotrophin receptor (p75NTR ) contributes to the disruption of the blood-retinal barrier in retinal ischemia. However, whether p75NTR influences the BBB permeability after acute cerebral ischemia remains unknown. The present study investigated the role and underlying mechanism of p75NTR on BBB integrity in an ischemic stroke mouse model, middle cerebral artery occlusion (MCAO). After 24 h of MCAO, astrocytes and endothelial cells in the infarct-affected brain area up-regulated p75NTR . Genetic p75NTR knockdown (p75NTR+/- ) or pharmacological inhibition of p75NTR using LM11A-31, a selective inhibitor of p75NTR , both attenuated brain damage and BBB leakage in MCAO mice. Astrocyte-specific conditional knockdown of p75NTR mediated with an adeno-associated virus significantly ameliorated BBB disruption and brain tissue damage, as well as the neurological functions after stroke. Further molecular biological examinations indicated that astrocytic p75NTR activated NF-κB and HIF-1α signals, which upregulated the expression of MMP-9 and vascular endothelial growth factor (VEGF), subsequently leading to tight junction degradation after ischemia. As a result, increased leukocyte infiltration and microglia activation exacerbated brain injury after stroke. Overall, our results provide novel insight into the role of astrocytic p75NTR in BBB disruption after acute cerebral ischemia. The p75NTR may therefore be a potential therapeutic target for the treatment of ischemic stroke.

Microbiopsy Sampling for Examining Age-Related Differences in Skeletal Muscle Fiber Morphology and Composition.

Introduction: The increasingly popular microbiopsy is an appealing alternative to the more invasive Bergström biopsy given the challenges associated with harvesting skeletal muscle in older populations. Parameters of muscle fiber morphology and composition derived from the microbiopsy have not been compared between young and older adults.Purpose: The purpose of this study was to examine muscle fiber morphology and composition in young (YM) and older (OM) males using the microbiopsy sampling technique. A secondary aim was to determine if specific strength is associated with serum levels of C-terminal agrin fragment [CAF; an indicator of neuromuscular junction (NMJ) degradation].Methods: Thirty healthy, YM (n = 15, age = 20.7 ± 2.2 years) and OM (n = 15, age = 71.6 ± 3.9 years) underwent ultrasound imaging to determine whole-muscle cross-sectional area (CSA) of the vastus lateralis and rectus femoris as well as isometric and isokinetic (60°⋅s–1 and 180°⋅s–1) peak torque testing of the knee extensors. Microbiopsy samples of the vastus lateralis were collected from 13 YM and 11 OM, and immunofluorescence was used to calculate CSA and proportion of type I and type II fibers.Results: Peak torque was lower in OM at all velocities (p ≤ 0.001; d = 1.39–1.86) but only lower at 180°⋅s–1 (p = 0.003; d = 1.23) when normalized to whole-muscle CSA. Whole-muscle CSA was smaller in OM (p = 0.001; d = 1.34), but atrophy was not present at the single fiber level (p > 0.05). Per individual, ∼900 fibers were analyzed, and type I fiber CSA was larger (p = 0.05; d = 0.94) in OM which resulted in a smaller type II/I fiber CSA ratio (p = 0.015; d = 0.95). CAF levels were not sensitive to age (p = 0.159; d = 0.53) nor associated with specific strength or whole-muscle CSA in OM.Conclusion: The microbiopsy appears to be a viable alternative to the Bergström biopsy for histological analyses of skeletal muscle in older adults. NMJ integrity was not influential for age-related differences in specific strength in our healthy, non-sarcopenic older sample.

Rotenone impairs learning and memory in mice through microglia-mediated blood brain barrier disruption and neuronal apoptosis

Rotenone is a neurotoxic pesticide widely used in agriculture. Dopaminergic neuron has long been considered as the target of rotenone. We recently reported that rotenone exposure also resulted in hippocampal and cortical neurodegeneration and cognitive dysfunction in mice. However, the mechanisms remain unknown. Here, we elucidated whether blood brain barrier (BBB) disruption and subsequent neuronal apoptosis mediated by microglial activation were involved in rotenone-elicited cognitive impairments. Results showed that rotenone dose-dependently elevated evens blue extravasation, fibrinogen accumulation and reduced expressions of tight junction proteins in the hippocampus and cortex of mice. Interestingly, microglial depletion and inactivation by PLX3397 and minocycline, respectively, markedly attenuated rotenone-elicited increase of BBB permeability, indicating a critical role of microglia. Furthermore, microglial depletion and inactivation were shown to abrogate rotenone-induced activation of matrix metalloproteinases 2 and 9 (MMP-2/-9), two important factors to regulate tight junction degradation and BBB permeability, in mice. Moreover, SB-3CT, a widely used MMP-2/-9 inhibitor, increased BBB integrity and simultaneously elevated expressions of tight junction proteins in rotenone-intoxicated mice. Finally, we found that SB-3CT significantly mitigated rotenone-induced neuronal apoptosis and synaptic loss as well as learning and memory impairments in mice. Altogether, this study revealed that rotenone elicited cognitive impairments in mice through microglia-mediated BBB disruption and neuronal apoptosis via MMP-2/-9, providing a novel aspect for the pathogenesis of pesticide-induced neurotoxicity and Parkinson's disease (PD)-related dementia.

Gate Voltage Pulse Rising Edge Dependent Dynamic Hot Carrier Degradation in Poly-Si Thin-Film Transistors

Dynamic degradation becomes a critical issue for thin-film transistors (TFTs) used in emerging new displays driven by high frequency gate voltage ${V}_{\text {G}}$ pulses. In this study, ${V}_{\text {G}}$ pulse rising edge dependent dynamic hot carrier degradation of poly-Si TFTs is investigated. It is demonstrated that rising edge of ${V}_{\text {G}}$ pulses which swing within the OFF-state of TFTs causes the degradation, while that of normal ${V}_{\text {G}}$ pulses which switch between the ON and OFF states across the flat band voltage ${V}_{\text {FB}}$ of TFTs does not. Based on transient TCAD simulation, the underlying mechanism of rising edge dependent degradation is proposed, which is based on the non-equilibrium PN junction degradation model previously proposed to explain ${V}_{\text {G}}$ pulse falling edge dependent degradation of poly-Si TFTs. Hence, the dynamic degradation model of poly-Si TFTs related to both rising and falling edge of the ${V}_{\text {G}}$ pulses can be unified now, which is applicable to fast gate pulses with steep rising and/or falling edges in sub- $\mu \text{s}$ level.

Prediction of Sarcopenia Using Multiple Biomarkers of Neuromuscular Junction Degeneration in Chronic Obstructive Pulmonary Disease.

Patients with chronic obstructive pulmonary disease (COPD) present with an advanced form of age-related muscle loss or sarcopenia. Among multiple pathomechanisms of sarcopenia, neuromuscular junction (NMJ) degradation may be of primary relevance. We evaluated the circulating biomarkers of NMJ degradation, including c-terminal agrin fragment -22 (CAF22), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) as predictors of sarcopenia in COPD during pulmonary rehabilitation (PR). Male, 61–77-year-old healthy controls and patients of COPD (n = 77–84/group) were recruited for measurements of circulating CAF22, BDNF, and GDNF levels. Functional assessment and measurements of plasma biomarkers were performed at diagnosis and following six months of PR. CAF22 levels were elevated while BDNF and GDNF levels were reduced in COPD patients at diagnosis, which were incompletely restored to normal levels following PR. These biomarkers showed varying degrees of associations with indexes of sarcopenia and functional recovery during PR. Logistic regression revealed that the combined use of three biomarkers enhanced the diagnostic accuracy of sarcopenia better than single biomarkers. Altogether, measurements of plasma CAF22, BDNF, and GDNF may be helpful for the accurate diagnosis of sarcopenia and functional capacity in COPD during PR.

Notoginsenoside R1 intervenes degradation and redistribution of tight junctions to ameliorate blood-brain barrier permeability by Caveolin-1/MMP2/9 pathway after acute ischemic stroke

BackgroundThe leakage of blood-brain barrier (BBB) is main pathophysiological change in acute stage of ischemic stroke, which not only deteriorates neurological function, but also increases the risk of hemorrhagic transformation after thrombolysis. Purpose/Study DesignThis article investigates the efficacy of Notoginsenoside R1, an active ingredient of Panax notoginseng, on BBB permeability and explores related mechanisms after acute ischemic stroke. MethodsIn vivo, male Sprague-Dawley rats (260–280 g) were selected and randomly divided into 6 groups: sham group, model group, low, middle and high doses of Notoginsenoside R1 groups and positive drug Dl-3-n-Butylphthalide group. Except for sham group, rats were performed with permanent middle cerebral artery occlusion model in each group. Twelve hours later, rats were evaluated for Bederson neurological function, and BBB integrity by Evans blue leak imaging; Triphenyltetrazolium chloride staining was used to detect the volume of cerebral infarction. Frozen sections of rats’ brain tissue were prepared for detection of MMPs activity in situ zymography. Peripheral tissue of cerebral infarction was collected and tested the expression of MMP2, 9 and tight junction proteins (zo1, claudin5, occludin) by western blot. In vitro, transwell endothelial barrier model was established by bEnd.3 cells. Oxygen glucose deprivation (OGD) was chosen to simulate the hypoxic environment. Suitable OGD stimulation time as well as Notoginsenoside R1 and Dl-3-n-Butylphthalide optimal dose concentrations were determined through transwell leakage and CCK8 assay. Furthermore, endothelial subcellular component proteins were extracted. The change of zo1, claudin5, occludin and caveolin1 was detected by western blot. ResultsNotoginsenoside R1 treatment significantly reduced BBB leakage and cerebral infarction volume, weakened neurological deficits in post-stroke rats. Moreover, it inhibited the activity of MMPs in infarcted cortex and striatum, down-regulated MMP2, 9 and up-regulated zo1 and claudin5 expressions in penumbra. In vitro, Notoginsenoside R1 treatment decreased OGD-induced endothelial barrier permeability, restored expressions of zo1, claudin5 on cellular membrane and cytoplasm, as well as mediated membrane redistribution of occludin and caveolin1 from actin cytoskeletal fraction. ConclusionsNotoginsenoside R1 treatment attenuates BBB permeability, cerebral infarction volume and neurological impairments in rats with acute cerebral ischemia. The mechanisms might be related to intervening degradation and redistribution of zo1, caludin5 and occludin by caveolin1/ MMP2/9 pathway. More effects and mechanisms of Notoginsenoside R1 on rehabilitation of stroke are worthy to be explored in the future.

Epithelial-to-Mesenchymal Transition and Neoangiogenesis in Laryngeal Squamous Cell Carcinoma.

Simple summaryThe mechanism of epithelial–mesenchymal transition is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, resulting in cellular junction degradation and increased cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. This study aimed to investigate a potential interplay between epithelial–mesenchymal transition and angiogenesis in laryngeal carcinoma. In our study, univariate Cox regression identified pN+ status and Slug expression as predictive of disease-free survival, while a trend toward significance emerged for CD105-assessed microvessel density and N-cadherin expression. In the multivariate Cox regression model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting disease-free survival. Data from our study support the hypothesis of a mutual concurrence of epithelial–mesenchymal transition and angiogenesis in the development of an aggressive phenotype in laryngeal squamous cell carcinoma.The mechanism of epithelial–mesenchymal transition (EMT) is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, comprising important events, such as cellular junction degradation, downregulation of epithelial phenotype markers, overexpression of mesenchymal markers, and increase in cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. The aim of this exploratory study was to investigate a potential interplay between EMT and angiogenesis (quantified through CD105 expression) in laryngeal carcinoma (LSCC). CD105-assessed microvessel density (MVD) and EMT markers (E-cadherin, N-cadherin, Snail, Slug, Zeb1, and Zeb2) were assessed on 37 consecutive LSCC cases. The univariate Cox regression model identified pN+ status (p = 0.0343) and Slug expression (p = 0.0268) as predictive of disease-free survival (DFS). A trend toward significance emerged for CD105-assessed MVD (p = 0.0869) and N-cadherin expression (p = 0.0911). In the multivariate Cox model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting DFS (p = 0.0346, p = 0.0430, and p = 0.0214, respectively). Our data support the hypothesis of a mutual concurrence of EMT and angiogenesis in driving LSCC cells toward an aggressive phenotype. To better characterize the predictive performance of prognostic models based on EMT and angiogenesis, further large-scale prospective studies are required.

Brain endothelial LRP1 maintains blood\u2013brain barrier integrity

The entry of blood-borne molecules into the brain is restricted by the blood–brain barrier (BBB). Various physical, transport and immune properties tightly regulate molecule movement between the blood and the brain to maintain brain homeostasis. A recent study utilizing a pan-endothelial, constitutive Tie2-Cre showed that paracellular passage of blood proteins into the brain is governed by endocytic and cell signaling protein low-density lipoprotein receptor–related protein 1 (LRP1). Taking advantage of conditional Slco1c1-CreERT2 specific to CNS endothelial cells and choroid plexus epithelial cells we now supplement previous results and show that brain endothelial Lrp1 ablation results in protease-mediated tight junction degradation, P-glycoprotein (P-gp) reduction and a loss of BBB integrity.

GYY4137 protected the integrity of the blood-brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis.

Injury to the blood-brain barrier (BBB) plays a vital role in sepsis-associated encephalopathy (SAE), which is one of the most common complications of sepsis. GYY4137, a new synthetic compound of hydrogen sulfide (H2 S), has extensive biological benefits. In this study, we focused on the protective effects of GYY4137 on the BBB in septic mice and the underlying mechanisms. The results suggested that whether administrated at the same time or 3hours after LPS injection, GYY4137 both significantly alleviated the clinical symptoms and the long-term prognosis. Besides, GYY4137 improved the pathological abnormalities of septic mice. Moreover, the degradation of tight junctions in the BBB was considerably inhibited by GYY4137. In addition, GYY4137 significantly attenuated inflammation and apoptosis in the brain. Furthermore, GYY4137 activated the Nrf2/ARE pathway through the sulfhydrylation of Keap1 and inhibited oxidative stress. ML385, the specific inhibitor of Nrf2, significantly reversed the protective effects of GYY4137 in sepsis mice. In conclusion, this study indicated that through the sulfhydrylation of Keap1, GYY4137 activated the Nrf2/ARE pathway and exerted anti-inflammatory, anti-apoptotic and antioxidant effects in septic mice that consequently protected the integrity of the BBB and improved the clinical outcome of sepsis. Our findings suggest that GYY4137 might be a promising agent for the treatment of SAE.

TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.

AimsEpidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm‐aging as a mediator and potential therapeutic target.Methods3 months‐ (young) and 18‐20 months‐old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF‐α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF‐ α were assessed in patients with ischemic stroke and correlated with age and outcome.ResultsOld mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood‐brain barrier in old mice, i.e. increased post‐stroke degradation of endothelial tight junctions and expression of tight junctions‐digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF‐α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF‐α plasma levels which correlated with worsened short‐term neurological outcome as well as with age.ConclusionsThis study identifies TNF‐α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm‐aging as a mechanism of age‐related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.

The Degradation of Airway Epithelial Tight Junctions in Asthma Under High Airway Pressure Is Probably Mediated by Piezo-1.

Full functioning of the airway physical barrier depends on cellular integrity, which is coordinated by a series of tight junction (TJ) proteins. Due to airway spasm, edema, and mucus obstruction, positive end-expiratory alveolar pressure (also termed auto-PEEP) is a common pathophysiological phenomenon, especially in acute asthma attack. However, the influence of auto-PEEP on small airway epithelial TJs is currently unclear. We performed studies to investigate the effect of extra pressure on small airway epithelial TJs and its mechanism. The results first confirmed that a novel mechanosensitive receptor, piezo-1, was highly expressed in the airway epithelium of asthmatic mice. Extra pressure induced the degradation of occludin, ZO-1 and claudin-18 in primary human small airway epithelial cells (HSAECs), resulting in a decrease in transepithelial electrical resistance (TER) and an increase in cell layer permeability. Through in vitro investigations, we observed that exogenous pressure stimulation could elevate the intracellular calcium concentration ([Ca2+]i) in HSAECs. Downregulation of piezo-1 with siRNA and pretreatment with BAPTA-AM or ALLN reduced the degradation of TJs and attenuated the impairment of TJ function induced by exogenous pressure. These findings indicate the critical role of piezo-1/[Ca2+]i/calpain signaling in the regulation of small airway TJs under extra pressure stimulation.

TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown

Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.

Highbush blueberry proanthocyanidins alleviate Porphyromonas gingivalis-induced deleterious effects on oral mucosal cells

Strong evidence points to Porphyromonas gingivalis, a Gram-negative anaerobic bacterium, as a keystone species in the development of the chronic form of periodontitis. The aim of the present study was to investigate the ability of highbush blueberry proanthocyanidins (PACs) to alleviate the P. gingivalis-induced deleterious effects on oral mucosal cells. We first showed that highbush blueberry PACs protect the integrity of the gingival keratinocyte barrier against P. gingivalis-mediated damage, as determined by measuring the transepithelial electrical resistance and paracellular flux of FITC-conjugated dextran. Moreover, the PACs prevented the translocation of P. gingivalis across the gingival keratinocyte barrier model. The proteinase activity of P. gingivalis was inhibited by the PACs suggesting that they may exert beneficial effects by reducing proteolytic degradation of the epithelial tight junctions. Regulation of gingival fibroblast inflammatory reactions may be one of the ways to prevent and control periodontal disease progression and severity. We showed that PACs significantly reduce IL-6 and IL-8 secretion by P. gingivalis-stimulated gingival fibroblasts. The present study showed the capacity of highbush blueberry PACs to protect the integrity of an in vitro model of gingival keratinocyte barrier against P. gingivalis, and to attenuate the secretion of pro-inflammatory cytokines by gingival fibroblasts infected with P. gingivalis. These results suggest beneficial effects of blueberry PACs thus supporting the need for future clinical trials on the potential of these bioactive molecules for periodontal disease prevention and/or treatment.

Degradation of copper‐plated silicon solar cells with damp heat stress

AbstractCrystalline silicon solar cells with copper‐plated contacts are fabricated, encapsulated in ethylene‐vinyl acetate (EVA), and subject to extended damp heat stress (85° C and 85% relative humidity). We source cell precursors from several different cell manufacturers and employ several different patterning methods of the silicon nitride layer and deposit a plated front contact stack of nickel, copper, and tin using light‐induced plating. Across different Cu‐plated samples, we find similar degradation that impacts both series resistance and diode quality of the cells, indicating that there is some degradation of the p‐n junction. The overall degradation is on the order of 15%–20% of maximum power (PMP), and roughly half of this degradation is attributable to degradation of the p‐n junction. Control samples with silver‐screenprinted contacts do not exhibit the same degradation, and p‐n junction degradation in copper‐plated samples is prevented by changing the encapsulant from EVA to a polyolefin. The degradation mode is hypothesized to be the diffusion of copper from the contact, followed by the transport of this copper into the silicon cell via some mechanism facilitated by the degraded EVA encapsulant.

The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions.

Ischemic stroke is a multi-factorial cerebrovascular disease with high worldwide morbidity and mortality. In the past few years, multiple studies have revealed the underlying mechanism of ischemia/reperfusion injury, including calcium overload, amino acid toxicity, oxidative stress, and inflammation. Connexin 43 (Cx43), the predominant connexin protein in astrocytes, has been recently proven to display non-substitutable roles in the pathology of ischemic stroke development and progression through forming gap junctions and hemichannels. Under normal conditions, astrocytic Cx43 could be found in hemichannels or in the coupling with other hemichannels on astrocytes, neurons, or oligodendrocytes to form the neuro–glial syncytium, which is involved in metabolites exchange between communicated cells, thus maintaining the homeostasis of the CNS environment. In ischemic stroke, the phosphorylation of Cx43 might cause the degradation of gap junctions and the opening of hemichannels, contributing to the release of inflammatory mediators. However, the remaining gap junctions could facilitate the exchange of protective and harmful metabolites between healthy and injured cells, protecting the injured cells to some extent or damaging the healthy cells depending on the balance of the exchange of protective and harmful metabolites. In this study, we review the changes in astrocytic Cx43 expression and distribution as well as the influence of these changes on the function of astrocytes and other cells in the CNS, providing new insight into the pathology of ischemic stroke injury; we also discuss the potential of astrocytic Cx43 as a target for the treatment of ischemic stroke.

Application of Human Induced Pluripotent Stem Cell-Derived Intestinal Organoids as a Model of Epithelial Damage and Fibrosis in Inflammatory Bowel Disease.

Inflammatory bowel disease, which typically manifests as Crohn's disease and ulcerative colitis, is caused by the abnormal production of cytokines such as tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β. These cytokines damage intestinal epithelial cells and trigger fibrosis, respectively, for which the current in vitro models have many limitations. Therefore, we tested whether human induced pluripotent stem cell-derived intestinal organoids (HiOs) can mimic inflammatory bowel disease (IBD), and whether such a model is suitable for drug screening. HiOs were treated with TNF-α and TGF-β to construct mucosal damage and fibrosis models. TNF-α diminished the mRNA expression of intestinal epithelial cell and goblet cell markers in HiOs. TNF-α also induced epithelial cell damage and degradation of tight junctions but not in the presence of infliximab, an antibody used in the clinic to deplete TNF-α. Furthermore, permeation of the non-absorbable marker FD-4 was observed in HiOs treated with TNF-α or ethylene glycol tetraacetic acid (EGTA), but not in the presence of infliximab. In contrast, TNF-α and TGF-β induced mRNA expression of mesenchymal and fibrosis markers, as well as epithelial-mesenchymal transition. SB431542, a TGF-β inhibitor, significantly reversed these events. The data indicate that HiOs mimic mucosal damage and fibrosis due to IBD and are thus suitable models for drug screening.

Dysregulation of intestinal epithelial CFTR-dependent Cl- ion transport and paracellular barrier function drives gastrointestinal symptoms of food-induced anaphylaxis in mice.

Food-triggered anaphylaxis can encompass a variety of systemic and intestinal symptoms. Murine-based and clinical studies have revealed a role for histamine and H1R and H2R-pathway in the systemic response; however, the molecular processes that regulate the gastrointestinal (GI) response are not as well defined. In the present study, by utilizing an IgE-mast cell (MC)-dependent experimental model of oral antigen-induced anaphylaxis, we define the intestinal epithelial response during a food-induced anaphylactic reaction. We show that oral allergen-challenge stimulates a rapid dysregulation of intestinal epithelial transcellular and paracellular transport that was associated with the development of secretory diarrhea. Allergen-challenge induced (1) a rapid intestinal epithelial Cftr-dependent Cl- secretory response and (2) paracellular macromolecular leak that was associated with modification in epithelial intercellular junction proteins claudin-1, 2, 3 and 5, E-cadherin and desmosomal cadherins. OVA-induced Cftr-dependent Cl- secretion and junctional protein degradation was rapid occurring and was sustained for 72 h following allergen-challenge. Blockade of both the proteolytic activity and Cl- secretory response was required to alleviate intestinal symptoms of food-induced anaphylaxis. Collectively, these data suggest that the GI symptom of food-induced anaphylactic reaction, secretory diarrhea, is a consequence of CFTR-dependent Cl- secretion and proteolytic activity.

Effect of gas atmospheres on degradation of MgO thin film magnetic tunneling junctions by deionized water

The degradation of the MgO thin film barrier of magnetic tunneling junctions caused by the dissolution of the film in deionized water during manufacturing processes is critical to the performance of spintronic devices. In this work, the influence of gas atmospheres including oxygen (O2), nitrogen (N2) and carbon dioxide (CO2) on dissolution behavior of the film was investigated by using X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic absorption spectroscopy (AAS). XPS depth profile results reveal that deionized water reacts with the film and infiltrates into the deeper layer of the film resulting in the chemical transformation of MgO to Mg(OH)2. AAS results confirm that the films dissolve because Mg2+ ions are released into deionized water. Consequently, Mg concentration in deionized water increases. It is found that the concentration of Mg2+ ions in deionized water is highest in the dissolution of CO2-saturated deionized water and lowest in those of N2-saturated deionized water. Simultaneously, the release of Mg2+ causes the development of the coral-like clusters over their surface and a decrease of the film thickness. XPS depth profile and SEM cross-sectional results demonstrate that the film thickness slightly decreases in sample N2 and decreases considerably in sample CO2. This is due to the fact that CO2 gas reacts with water, reducing its pH and thus increasing of the dissolution rate, while N2 gas has no reaction with water. Finally, this work proposes a qualitative model based on chemical reaction to explain the dissolution behavior of the film.

Superstrate Structured FTO/TiO2/In2S3/Cu2ZnSnS4 Solar Cells Fabricated by a Spray Method with Aqueous Solutions

Copper Zinc Tin Sulfide (C2ZTS4) solar cells have become a fascinating research topic due to several advantages of the C2ZTS4 absorber layer, such as having non-toxic and abundantly available components. Superstrate structured C2ZTS4 solar cells were fabricated on the top of a fluorine-doped tin oxide (FTO) substrate with a spray pyrolysis method from the window layer to the absorber layer. Titanium dioxide (TiO2) and indium sulfide (In2S3) were used as the window and buffer layer, respectively. The source materials for the C2ZTS4 and buffer layers were all aqueous-based solutions. The metallic component ratio, Cu/(Zn + Sn), and the sulfur concentration in the solutions were systematically investigated. The optimum ratio of Cu/(Zn + Sn) in the film is about 0.785, while 0.18 M thiourea in the solution is the best condition for high performance. The C2ZTS4 layers deposited at lower temperatures (<360 °C) yielded a low quality resulting in low current density (JSC). On the other hand, the C2ZTS4 layers deposited at high temperature (~400 °C) showed a low fill factor (FF) without degradation of the open-circuit voltage (VOC) and JSC due to the junction degradation and high contact resistance between the absorber layer and metal contact. The best cell efficiency, VOC, JSC, and fill factor achieved were 3.34%, 383 mV, 24.6 mA/cm2, and 37.7%, respectively.

Safe Focused Ultrasound-Mediated Blood-Brain Barrier Opening and Repair is Not Mediated by Tight Junction Degradation

Focused ultrasound (FUS) with microbubbles opens the blood-brain barrier (BBB) to allow targeted drug delivery into the brain; however, the mechanisms of BBB opening and the response of the neurovascular unit at either low acoustic pressures, known to open the BBB transiently, or high pressures that cause brain damage, remain unclear. Employing a transgenic mouse strain where tight junctions (TJs) are labelled with eGFP, we examined TJ strand morphology at 1 and 72 hours post-FUS at both low and high pressures. We find that transient BBB opening due to FUS is not caused by TJ strand damage, unless FUS is used at high pressures, and this is localized primarily in arterioles and capillaries. At high pressures, TJ strands are obliterated and remain unrepaired even at 72 hours, allowing for fibrinogen passage, and persistent microglial activation. Our findings suggest that at low safe pressures, upregulation of transcytosis may likely increase transiently BBB permeability to deliver therapeutics to the brain.