Phospholipid Bilayer Inspired Sandwich Structural Nanofibrous Membrane for Atmospheric Water Harvesting and Selective Release.

Atmospheric water harvesting (AWH) has been broadly exploited to meet the challenge of water shortage. Despite the significant achievements of AWH, the leakage of hydroscopic salt during the AWH process hinders its practical applications. Herein, inspired by the unique selective permeability of the phospholipid bilayer, a sandwich structural (hydrophobic-hydrophilic-hydrophobic) polyacrylonitrile nanofibrous membrane (San-PAN) was fabricated for AWH. The hydrophilic inner layer loaded with LiCl could capture water from the air. The hydrophobic microchannels in the outer layer could selectively allow the free transmission of gaseous water molecules but confine the hydroscopic salt solution in the hydrophilic layer, achieving continuous and recyclable water sorption/desorption. As demonstrated, the as-prepared AWH devices presented high-efficient adsorption kinetics from 1.66 to 4.08 g g-1 at 30% to 90% relative humidity. Thus, this work strengthens the understanding of the water transmission process along microchannels and provides insight into the practical applications of AWH.

Capsaicin inhibits A7r5 cell senescence via the mitochondrial carrier protein Slc25a12.

Aging of vascular smooth muscle cells (VSMCs) is the principal factor responsible for the loss of vascular function, and continuous exposure to high glucose is one of the key factors contributing to the aging of VSMCs. This study established a high glucose-induced senescence model of the A7r5 cell line and used transcriptome sequencing to screen the regulatory target genes of high glucose-induced cellular senescence. The study revealed that the expression of the Slc25a12 gene, which belongs to the solute carrier family 25 member 12, was notably reduced following damage caused by high glucose levels. This inhibition was shown to cause mitochondrial malfunction and cellular senescence. The encoded product of the Slc25a12 gene is a mitochondrial carrier protein that binds to calcium and aids in transporting aspartate for glutamate exchange within the inner mitochondrial membrane. Mitochondrial dysfunction compromises the cell's capacity to resist oxidation and repair damage, and is an inherent element in hastening cellular aging. Moreover, our findings validated that the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin hindered the decrease in Slc25a12 expression, prevented mitochondrial dysfunction, and blocked cellular senescence. Could the regulation of Slc25a12 expression by capsaicin restore cellular mitochondrial function and restrict senescence? In vitro tests have verified that interference with A7r5 Slc25a12 noticeably diminishes capsaicin's effectiveness in repairing mitochondrial function and inhibiting senescence. The findings indicate that capsaicin delays mitochondrial dysfunction and therefore hinders cellular senescence by regulating the mitochondrial membrane protein Slc25a12 in the A7r5 cell line.

TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease.

As the brain-resident innate immune cells, reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia is still unclear in AD pathogenesis. Here, using metabolic profiling, we show that microglia energy metabolism is significantly suppressed during chronic Aß-tolerant processes including oxidative phosphorylation and aerobic glycolysis via the mTOR-AKT-HIF-1α pathway. Pharmacological activation of TRPV1 rescues Aß-tolerant microglial dysfunction, the AKT/mTOR pathway activity, and metabolic impairments and restores the immune responses including phagocytic activity and autophagy function. Amyloid pathology and memory impairment are accelerated in microglia-specific TRPV1-knockout APP/PS1 mice. Finally, we showed that metabolic boosting with TRPV1 agonist decreases amyloid pathology and reverses memory deficits in AD mice model. These results indicate that TRPV1 is an important target regulating metabolic reprogramming for microglial functions in AD treatment.

The aberrant levels of decorin induce damages of human salivary gland epithelial cells and polarization of macrophages.

OBJECTIVES: This study aimed to preliminarily address the levels of decorin (DCN, a critical component of extracellular matrix) and its potential roles in primary Sjögren's syndrome (pSS). METHODS: DCN levels were determined in the salivary glands of experimental SS (ESS) mice and pSS patients by RNA sequencing, bioinformatics analysis, or immunohistochemical staining. Its correlation with interested genes and co-localization with a putative receptor was studied in pSS patients. In addition, its potential roles on salivary gland epithelium and macrophages were tested by exogenous administration to corresponding cell lines, followed by the evaluation of apoptosis using flow cytometry or cytokine expression using quantitative real-time polymerase chain reaction. RESULTS: Our data revealed a significant elevation of DCN in the salivary glands of the ESS mice model and pSS patients. In addition, the bioinformatics analysis of DCN in the GSE40611 (RNA-seq, parotid glands) dataset displayed an elevation of the DCN level in the parotid glands of pSS patients that positively correlated with several chemokines (CXCL13, CXCL9, and CCL20), Interleukin -1 ß (IL1 -ß), and caspase3 but negatively correlated with the proliferation relative gene MKI67. The stimulatory effects of DCN on the salivary gland epithelial cells (A253 cell line) and macrophages have been determined as they are considered active participants in the progression of SS. The data showed that DCN induced the apoptosis of A253 cells and polarization of macrophages towards the M1 phenotype, characterized by the expression of pro-inflammatory cytokines. CONCLUSIONS: Our study provided preliminary evidence to understand the clinical significance of DCN in pSS and broadened our horizons in understanding the mechanism of pSS.

A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson's disease.

BACKGROUND: The α-synuclein released by neurons activates microglia, which then engulfs α-synuclein for degradation via autophagy. Reactive microglia are a major pathological feature of Parkinson's disease (PD), although the exact role of microglia in the pathogenesis of PD remains unclear. Transient receptor potential vanilloid type 1 (TRPV1) channels are nonselective cation channel protein that have been proposed as neuroprotective targets in neurodegenerative diseases. METHODS: Using metabolic profiling, microglia energy metabolism was measured including oxidative phosphorylation and aerobic glycolysis. The mRFP-GFP-tagged LC3 reporter was introduced to characterize the role of TRPV1 in microglial autophagy. α-synuclein preformed fibril (PFF) TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD were employed to study the capacity of TRPV1 activation to attenuate neurodegeneration process. RESULTS: We found that acute exposure to PFF caused microglial activation as a result of metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis via the AKT-mTOR-HIF-1α pathway. Activated microglia eventually reached a state of chronic PFF-tolerance, accompanied by broad defects in energy metabolism. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued metabolic impairments in PFF-tolerant microglia and also defects in mitophagy caused by disruption of the AKT-mTOR-HIF-1α pathway. Capsaicin attenuated phosphorylation of α-synuclein in primary neurons by boosting phagocytosis in PFF-tolerant microglia in vitro. Finally, we found that behavioral deficits and loss of dopaminergic neurons were accelerated in the PFF TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD. We identified defects in energy metabolism, mitophagy and phagocytosis of PFF in microglia from the substantia nigra pars compacta of TRPV1flox/flox; Cx3cr1Cre mice. CONCLUSION: The findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD.

Appetitive Memory with Survival Benefit Is Robust Across Aging in Drosophila.

The formation of memory declines with advancing age. However, susceptibility to memory impairments depends on several factors, including the robustness of memory, the responsible neural circuits, and the internal state of aged individuals. How age-dependent changes in internal states and neural circuits affect memory formation remains unclear. Here, we show in Drosophila melanogaster that aged flies of both sexes form robust appetitive memory conditioned with nutritious sugar, which suppresses their high mortality rates during starvation. In contrast, aging impairs the formation of appetitive memory conditioned with non-nutritious sugar that lacks survival benefits for the flies. We found that aging enhanced the preference for nutritious sugar over non-nutritious sugar correlated with an age-dependent increase in the expression of Drosophila neuropeptide F, an ortholog of mammalian neuropeptide Y. Furthermore, a subset of dopaminergic neurons that signal the sweet taste of sugar decreases its function with aging, while a subset of dopaminergic neurons that signal the nutritional value of sugar maintains its function with age. Our results suggest that aging impairs the ability to form memories without survival benefits; however, the ability to form memories with survival benefits is maintained through age-dependent changes in the neural circuits and neuropeptides.SIGNIFICANCE STATEMENT The susceptibility to age-dependent memory impairments depends on the strength of the memory, changes in the responsible neurons, and internal states of aged individuals. How age-dependent changes in such internal states affect neural activity and memory formation remains unclear. We show in Drosophila melanogaster that aged flies of both sexes form robust appetitive memory conditioned with nutritious sugar, which has survival benefits for aged flies. In contrast, aging impairs the formation of appetitive memory conditioned with non-nutritious sugar that lacks survival benefits for the flies. Aging changes the neural circuits including dopamine neurons and neuropeptide F-expressing neurons, leading to the age-dependent impairment in memory with insufficient survival benefits and the preservation of the ability to form memory with survival benefits.

Clinical characteristics on admission predict in-hospital fatal outcome in patients aged ≥75 years with novel coronavirus disease (COVID-19): a retrospective cohort study.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) has become a worldwide pandemic and precise fatality data by age group is needed urgently. This study to delineate the clinical characteristics and outcome of COVID-19 patients aged ≥75 years and identify the risk factors of in-hospital death. METHODS: A total of 141 consecutive patients aged ≥75 years who were admitted to the hospital between 12th and 19th February 2020. In-hospital death, clinical characteristics and laboratory findings on admission were obtained from medical records. The final follow-up observation was on the 31st March 2020. RESULTS: The median age was 81 years (84 female, 59.6%). Thirty-eight (27%) patients were classified as severe or critical cases. 18 (12.8%) patients had died in hospital and the remaining 123 were discharged. Patients who died were more likely to present with fever (38.9% vs. 7.3%); low percutaneous oxygen saturation (SpO2) (55.6% vs. 7.3%); reduced lymphocytes (72.2% vs. 35.8%) and platelets (27.8% vs. 4.1%); and increased D-dimer (94.4% vs. 42.3%), creatinine (50.0% vs. 22.0%), lactic dehydrogenase (LDH) (77.8% vs. 30.1%), high sensitivity troponin I (hs-TnI) (72.2% vs. 14.6%), and N-terminal pro-brain natriuretic peptide (NT-proBNP) (72.2% vs. 6.5%; all P < 0.05) than patients who recovered. Male sex (odds ratio [OR] = 13.1, 95% confidence interval [CI] 1.1 to 160.1, P = 0.044), body temperature > 37.3 °C (OR = 80.5, 95% CI 4.6 to 1407.6, P = 0.003), SpO2 ≤ 90% (OR = 70.1, 95% CI 4.6 to 1060.4, P = 0.002), and NT-proBNP> 1800 ng/L (OR = 273.5, 95% CI 14.7 to 5104.8, P < 0.0001) were independent risk factors of in-hospital death. CONCLUSIONS: In-hospital fatality among elderly COVID-19 patients can be estimated by sex and on-admission measurements of body temperature, SpO2, and NT-proBNP.

Comparative Study on Noise Reduction Effect of Fiber Optic Hydrophone Based on LMS and NLMS Algorithm.

Adaptive filtering has the advantages of real-time processing, small computational complexity, and good adaptability and robustness. It has been widely used in communication, navigation, signal processing, optical fiber sensing, and other fields. In this paper, by adding an interferometer with the same parameters as the signal interferometer as the reference channel, the sensing signal of the interferometric fiber-optic hydrophone is denoised by two adaptive filtering schemes based on the least mean square (LMS) algorithm and the normalized least mean square (NLMS) algorithm respectively. The results show that the LMS algorithm is superior to the NLMS algorithm in reducing total harmonic distortion, improving the signal-to-noise ratio and filtering effect.

KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3ß pathway.

Neuroinflammation may induce a phenotype switch to reactive astrogliosis in neurodegenerative disorders. The calcium-activated potassium channel (KCa3.1) is active in the phenotypic switch that occurs during astrogliosis in Alzheimer's disease and ischemic stroke. Here, transcriptome sequencing (RNA-Seq), immunohistochemistry, western blotting, pharmacological blockade, and calcium imaging were used to investigate astrocyte KCa3.1 activity in neuroinflammation, Tau accumulation, and insulin signaling deficits in male wild-type C57BL/6 and KCa3.1-/- knockout (KO) mice, and in primary astrocyte cultures. KCa3.1 deficiency in KO mice decreased lipopolysaccharide (LPS)-induced memory deficits, neuronal loss, glial activation, Tau phosphorylation, and insulin signaling deficits in vivo. KCa3.1 expression in astrocytes was associated with LPS-induced upregulation of the Orai1 store-operated Ca2+ channel protein. The KCa3.1 channel was found to regulate store-operated Ca2+ overload through an interaction with Orai1 in LPS-induced reactive astrocytes. The LPS-induced effects on KCa3.1 and Orai1 indirectly promoted astrogliosis-related changes via the PI3K/AKT/GSK3ß and NF-κB signaling pathways in vitro. Unbiased evaluation of RNA-Seq results for actively translated RNAs confirmed that substantial astrocyte diversity was associated with KCa3.1 deficiency. Our results suggest that KCa3.1 regulated astrogliosis-mediated neuroinflammation, Tau accumulation, and insulin signaling deficiency via PI3K/AKT/GSK3ß and NF-κB signaling pathways, and contributing to neuronal loss and memory deficits in this neuroinflammation mouse model.

Predicting Alzheimer Disease From Mild Cognitive Impairment With a Deep Belief Network Based on 18F-FDG-PET Images.

OBJECTIVE: Accurate diagnosis of early Alzheimer disease (AD) plays a critical role in preventing the progression of memory impairment. We aimed to develop a new deep belief network (DBN) framework using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) metabolic imaging to identify patients at the mild cognitive impairment (MCI) stage with presymptomatic AD and to discriminate them from other patients with MCI. METHODS: 18F-fluorodeoxyglucose-PET images of 109 patients recruited in the ongoing longitudinal Alzheimer's Disease Neuroimaging Initiative study were included in this analysis. Patients were grouped into 2 classes: (1) stable mild cognitive impairment (n = 62) or (2) progressive mild cognitive impairment (n = 47). Our framework is composed of 4 steps: (1) image preprocessing: normalization and smoothing; (2) identification of regions of interest (ROIs); (3) feature learning using deep neural networks; and (4) classification by support vector machine with 3 kernels. All classification experiments were performed with a 5-fold cross-validation. Accuracy, sensitivity, and specificity were used to validate the results. RESULT: A total of 1103 ROIs were obtained. One hundred features were learned from ROIs using the DBN. The classification accuracy using linear, polynomial, and RBF kernels was 83.9%, 79.2%, and 86.6%, respectively. This method may be a powerful tool for personalized precision medicine in the population with prediction of early AD progression.

The potassium channel KCa3.1 represents a valid pharmacological target for microgliosis-induced neuronal impairment in a mouse model of Parkinson's disease.

BACKGROUND: Recent studies described a critical role for microglia in Parkinson's disease (PD), where these central nerve system resident immune cells participate in the neuroinflammatory microenvironment that contributes to dopaminergic neurons loss in the substantia nigra. Understanding the phenotype switch of microgliosis in PD could help to identify the molecular mechanism which could attenuate or delay the progressive decline in motor function. KCa3.1 has been reported to regulate the "pro-inflammatory" phenotype switch of microglia in neurodegenerative pathological conditions. METHODS: We here investigated the effects of gene deletion or pharmacological blockade of KCa3.1 activity in wild-type or KCa3.1-/- mice after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mouse model of PD. MPTP-induced PD mouse model was subjected to the rotarod test to evaluate the locomotor ability. Glia activation and neuron loss were measured by immunostaining. Fluo-4 AM was used to measure cytosolic Ca2+ level in 1-methyl-4-phenylpyridinium (MPP+)-induced microgliosis in vitro. RESULTS: We report that treatment of MPTP-induced PD mouse model with gene deletion or pharmacological blockade of KCa3.1 with senicapoc improves the locomotor ability and the tyrosine hydroxylase (TH)-positive neuron number and attenuates the microgliosis and neuroinflammation in the substantia nigra pars compacta (SNpc). KCa3.1 involves in store-operated Ca2+ entry-induced Ca2+ overload and endoplasmic reticulum stress via the protein kinase B (AKT) signaling pathway during microgliosis. Gene deletion or blockade of KCa3.1 restored AKT/mammalian target of rapamycin (mTOR) signaling both in vivo and in vitro. CONCLUSIONS: Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in PD.

SPION-mediated miR-141 promotes the differentiation of HuAESCs into dopaminergic neuron-like cells via suppressing lncRNA-HOTAIR.

In this study, a bioinformatics analysis and luciferase reporter assay revealed that microRNA-141 could silence the expression of lncRNA-HOTAIR by binding to specific sites on lncRNA-HOTAIR. We used superparamagnetic iron oxide nanoparticles (SPIONs) to mediate the high expression of microRNA-141 (SPIONs@miR-141) in human amniotic epithelial stem cells (HuAESCs), which was followed by the induction of the differentiation of HuAESCs into dopaminergic neuron-like cells (iDNLCs). qPCR, western blot, immunofluorescence staining and HPLC all suggested that SPION-mediated overexpression of miR-141 could promote an increased expression of brain-derived neurotrophic factor (BDNF), DAT and 5-TH in HuAESC-derived iDNLCs. The RIP and ChIP assay also showed that overexpression of miR-141 could significantly inhibit the recruitment and binding of lncRNA-HOTAIR to EZH2 on BDNF gene promoter. cDNA microarray analysis revealed that the expression levels of 190 genes were much higher in iDNLCs than in HuAESCs. Finally, a protein interaction network analysis and identification showed that in the iDNLC group with SPIONs@miR-141, factors that interact with BDNF, such as FGF8, SHH, NTRK3 and CREB1, all showed significantly higher expression levels compared with those in the SPIONs@miR-Mut. Therefore, this study confirmed that the highly efficient expression of microRNA-141 mediated by SPIONs could improve the efficiency of HuAESCs differentiation into dopaminergic neuron-like cells.

DNA-Conjugated Amphiphilic Aggregation-Induced Emission Probe for Cancer Tissue Imaging and Prognosis Analysis.

Detection of an ultralow concentration of mRNA is important in the prognosis of gene-related diseases. In this study, a DNA-conjugated amphiphilic aggregation-induced emission probe (TPE-R-DNA) was synthesized for cancer tissue imaging and prognosis analysis based on an exonuclease III-aided target recycling technique. TPE-R-DNA comprise two components: a hydrophobic component that serves as the "turn-on" long wavelength fluorescence imaging agent (TPE-R-N3); and a hydrophilic single DNA strand (Alk-DNA) which acts as specific recognition part for target mRNA. In the absence of target mRNA, TPE-R-DNA had almost no fluorescence because of its high water solubility. Conversely, the TPE-R-DNA was digested by exonuclease III (Exo III) in the presence of MnSOD mRNA to release the hydrophobic fluorogens (TPE-R-AT). Subsequently, TPE-R-AT formed aggregates, and therefore, fluorescence signal was distinctly observed. For the first time, the structure of the hydrolysis product (TPE-R-AT), containing two bases A and T, was proved by the mass spectrum (MS) and high-performance liquid chromatography (HPLC). Moreover, the detection limit toward mRNA could be achieved in as low as 0.6 pM. Furthermore, the fluorescent signal can be used to confirm the MnSOD mRNA expression level in cancer tissue. The MnSOD mRNA expression in renal cancer was lower than in renal cancer adjacent tissue. In particular, the expression level was analyzed to predict prognosis of cancer patients. Our results demonstrate that a shorter survival time was evident among patients in lower MnSOD mRNA expression. Thereby, it indicates great potential for the development of an ultrasensitive biosensing platform for the application in disease prognosis.

Ca2+-dependent endoplasmic reticulum stress correlation with astrogliosis involves upregulation of KCa3.1 and inhibition of AKT/mTOR signaling.

BACKGROUND: The intermediate-conductance Ca2+-activated K+ channel KCa3.1 was recently shown to control the phenotype switch of reactive astrogliosis (RA) in Alzheimer's disease (AD). METHODS: KCa3.1 channels expression and cell localization in the brains of AD patients and APP/PS1 mice model were measured by immunoblotting and immunostaining. APP/PS1 mice and KCa3.1-/-/APP/PS1 mice were subjected to Morris water maze test to evaluate the spatial memory deficits. Glia activation and neuron loss was measured by immunostaining. Fluo-4AM was used to measure cytosolic Ca2+ level in ß-amyloid (Aß) induced reactive astrocytes in vitro. RESULTS: KCa3.1 expression was markedly associated with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in both Aß-stimulated primary astrocytes and brain lysates of AD patients and APP/PS1 AD mice. The KCa3.1 channel was shown to regulate store-operated Ca2+ entry (SOCE) through an interaction with the Ca2+ channel Orai1 in primary astrocytes. Gene deletion or pharmacological blockade of KCa3.1 protected against SOCE-induced Ca2+ overload and ER stress via the protein kinase B (AKT) signaling pathway in astrocytes. Importantly, gene deletion or blockade of KCa3.1 restored AKT/mechanistic target of rapamycin signaling both in vivo and in vitro. Consistent with these in vitro data, expression levels of the ER stress markers 78-kDa glucose-regulated protein and CCAAT/enhancer-binding protein homologous protein, as well as that of the RA marker glial fibrillary acidic protein were increased in APP/PS1 AD mouse model. Elimination of KCa3.1 in KCa3.1-/-/APP/PS1 mice corrected these abnormal responses. Moreover, glial activation and neuroinflammation were attenuated in the hippocampi of KCa3.1-/-/APP/PS1 mice, as compared with APP/PS1 mice. In addition, memory deficits and neuronal loss in APP/PS1 mice were reversed in KCa3.1-/-/APP/PS1 mice. CONCLUSIONS: Overall, these results suggest that KCa3.1 is involved in the regulation of Ca2+ homeostasis in astrocytes and attenuation of the UPR and ER stress, thus contributing to memory deficits and neuronal loss.

The potassium channel KCa3.1 constitutes a pharmacological target for astrogliosis associated with ischemia stroke.

BACKGROUND: Reactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-ß-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease. METHODS: Wild type mice and KCa3.1-/- mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro. RESULTS: Immunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1-/- mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1-/- pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis. CONCLUSIONS: Our data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.

Low-power all-optical microwave filter with tunable central frequency and bandwidth based on cascaded opto-mechanical microring resonators.

We propose and experimentally demonstrate an all-optical microwave filter with tunable central frequency and bandwidth based on two cascaded silicon opto-mechanical microring resonators (MRRs). Due to the Vernier effect, transmission spectrum of the cascaded MRRs is a series of notch bimodal distribution. In the case of intensity modulation with optical double-sideband (ODSB) signals, the optical carrier is fixed between the two resonant peaks of one notch bimodal distribution. By injecting two pump powers to control the above two resonance red-shifts based on the nonlinear effects in opto-mechanical MRRs, the frequency intervals between the optical carrier and the two resonances could be flexibly manipulated for tunable microwave processing. In the experiment, with the highest required pump powers of 1.65 mW and 0.96 mW, the central frequency and bandwidth of the notch microwave photonic filter (MPF) could be tuned from 5 GHz to 36 GHz and 6.7 GHz to 10.3 GHz, respectively. The proposed opto-mechanical device is competent to process microwave signals with dominant advantages of all-optical control, compact footprint, wide tuning range and low-power consumption, which has significant applications in on-chip microwave systems.

KCa3.1 constitutes a pharmacological target for astrogliosis associated with Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia and is characterized by a progression from decline of episodic memory to a global impairment of cognitive function. Astrogliosis is a hallmark feature of AD, and reactive gliosis has been considered as an important target for intervention in various neurological disorders. We previously found in astrocyte cultures that the expression of the intermediate conductance calcium-activated potassium channel KCa3.1 was increased in reactive astrocytes induced by TGF-ß, while pharmacological blockade or genetic deletion of KCa3.1 attenuated astrogliosis. In this study, we sought to suppress reactive gliosis in the context of AD by inhibiting KCa3.1 and evaluate its effects on the cognitive impairment using murine animal models such as the senescence-accelerated mouse prone 8 (SAMP8) model that exhibits some AD-like symptoms. We found KCa3.1 expression was increased in reactive astrocytes as well as neurons in the brains of both SAMP8 mice and Alzheimer's disease patients. Blockade of KCa3.1 with the selective inhibitor TRAM-34 in SAMP8 mice resulted in a decrease in astrogliosis as well as microglia activation, and moreover an attenuation of memory deficits. Using KCa3.1 knockout mice, we further confirmed that deletion of KCa3.1 reduced the activation of astrocytes and microglia, and rescued the memory loss induced by intrahippocampal Aß1-42 peptide injection. We also found in astrocyte cultures that blockade of KCa3.1 or deletion of KCa3.1 suppressed Aß oligomer-induced astrogliosis. Our data suggest that KCa3.1 inhibition might represent a promising therapeutic strategy for AD treatment.

A mucoactive drug carbocisteine ameliorates steroid resistance in rat COPD model.

Steroid insensitivity has been commonly found in chronic obstructive pulmonary disease (COPD) patients, which is mediated by the reduction of histone deacetylase (HDAC) 2. Here we aimed to establish a steroid resistant model on experimental COPD rats and evaluate the effect of carbocisteine (S-CMC), a mucoactive drug. Exposure to cigarette smoke (CS) caused marked pathological features of COPD which are insensitive to DEX associated with the down-regulation of HDAC2 expression/activity. The DEX insensitivity observed in COPD featured rats was improved by S-CMC in the aspects of inhibiting chronic lung inflammation (total and differential inflammatory cell counts, inflammatory cytokines release and inflammatory cells infiltration); ameliorating airway remodeling (thickness of airway epithelium and smooth muscle, airway fibrosis, and the level of α-SMA and TGF-ß1); improving emphysema (emphysema index D2, level of MMP-9 in BALF and the expression of alpha-1 antitrypsin) and preventing impairments of lung function (PEF, IP and IP-slope). Simultaneously, down-regulation of HDAC2 expression/activity was ameliorated by S-CMC treatment. These results indicate that the rat COPD model with steroid resistance was established by active smoking in a short time frame and demonstrate that the failure of steroid therapy can be restored by S-CMC accompanied by increasing HDAC2 expression/activity, providing additional evidence that S-CMC might be used for GC resistance in COPD.

Carbocysteine restores steroid sensitivity by targeting histone deacetylase 2 in a thiol/GSH-dependent manner.

Steroid insensitivity is commonly observed in patients with chronic obstructive pulmonary disease. Here, we report the effects and mechanisms of carbocysteine (S-CMC), a mucolytic agent, in cellular and animal models of oxidative stress-mediated steroid insensitivity. The following results were obtained: oxidative stress induced higher levels of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α), which are insensitive to dexamethasone (DEX). The failure of DEX was improved by the addition of S-CMC by increasing histone deacetylase 2 (HDAC2) expression/activity. S-CMC also counteracted the oxidative stress-induced increase in reactive oxygen species (ROS) levels and decreases in glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, oxidative stress-induced events were decreased by the thiol-reducing agent dithiothreitol (DTT), enhanced by the thiol-oxidizing agent diamide, and the ability of DEX was strengthened by DTT. In addition, the oxidative stress-induced decrease in HDAC2 activity was counteracted by S-CMC by increasing thiol/GSH levels, which exhibited a direct interaction with HDAC2. S-CMC treatment increased HDAC2 recruitment and suppressed H4 acetylation of the IL-8 promoter, and this effect was further ablated by addition of buthionine sulfoximine, a specific inhibitor of GSH synthesis. Our results indicate that S-CMC restored steroid sensitivity by increasing HDAC2 expression/activity in a thiol/GSH-dependent manner and suggest that S-CMC may be useful in a combination therapy with glucocorticoids for treatment of steroid-insensitive pulmonary diseases.

Targeted inhibition of KCa3.1 attenuates TGF-ß-induced reactive astrogliosis through the Smad2/3 signaling pathway.

Reactive astrogliosis, characterized by cellular hypertrophy and various alterations in gene expression and proliferative phenotypes, is considered to contribute to brain injuries and diseases as diverse as trauma, neurodegeneration, and ischemia. KCa3.1 (intermediate-conductance calcium-activated potassium channel), a potassium channel protein, has been reported to be up-regulated in reactive astrocytes after spinal cord injury in vivo. However, little is known regarding the exact role of KCa3.1 in reactive astrogliosis. To elucidate the role of KCa3.1 in regulating reactive astrogliosis, we investigated the effects of either blocking or knockout of KCa3.1 channels on the production of astrogliosis and astrocytic proliferation in response to transforming growth factor (TGF)-ß in primary cultures of mouse astrocytes. We found that TGF-ß increased KCa3.1 protein expression in astrocytes, with a concomitant marked increase in the expression of reactive astrogliosis, including glial fibrillary acidic protein and chondroitin sulfate proteoglycans. These changes were significantly attenuated by the KCa3.1 inhibitor 1-((2-chlorophenyl) (diphenyl)methyl)-1H-pyrazole (TRAM-34). Similarly, the increase in glial fibrillary acidic protein and chondroitin sulfate proteoglycans in response to TGF-ß was attenuated in KCa3.1(-/-) astrocytes. TRAM-34 also suppressed astrocytic proliferation. In addition, the TGF-ß-induced phosphorylation of Smad2 and Smad3 proteins was reduced with either inhibition of KCa3.1 with TRAM-34 or in KCa3.1(-/-) astrocytes. These findings highlight a novel role for the KCa3.1 channel in reactive astrogliosis phenotypic modulation and provide a potential target for therapeutic intervention for brain injuries. Reactive astrogliosis is characterized by the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans. We demonstrate that either pharmacological blockade or knockout of KCa3.1 channels reduces reactive gliosis in cultured astrocytes caused by TGF-ß, and also reduces TGF-ß-induced phosphorylation of Smad2/3.