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Piezoceramic transducers (PCTs) bonded to carbon fiber-reinforced plastic (CFRP) composite structures must be durable as well as remain properly bonded to the structure in order to provide reliable data for accurate guided-wave-based structural health monitoring (SHM) of aeronautical components. The current method of bonding transducers to composite structures through epoxy adhesives faces some shortcomings, such as difficult reparability, lack of weldability, longer curing cycles, and shorter shelf life. To overcome these shortcomings, a new efficient procedure for bonding the transducers to thermoplastic (TP) composite structures was developed by utilizing TP adhesive films. Application-suitable TP films (TPFs) were identified and characterized through standard differential scanning calorimetry (DSC) and single lap shear (SLS) tests to study their melting behavior and bonding strength, respectively. Special PCTs called acousto-ultrasonic composite transducers (AUCTs) were bonded to high-performance TP composites (carbon fiber Poly-Ether-Ether-Ketone) coupons with a reference adhesive (Loctite EA 9695) and the selected TPFs. The integrity and durability of the bonded AUCTs in aeronautical operational environmental conditions (AOEC) were assessed in accordance to the standard Radio Technical Commission for Aeronautics DO-160. The AOEC tests performed were operating low and high temperatures, thermal cycling, hot-wet, and fluid susceptibility tests. The health and bonding quality of the AUCTs were evaluated by the electro-mechanical impedance (EMI) spectroscopy method and ultrasonic inspections. The AUCT defects were created artificially and their influence on the susceptance spectra (SS) was measured to compare them with the AOEC-tested AUCTs. The results show that a small change occurred in the SS characteristics of the bonded AUCTs in all of the adhesive cases after the AOEC tests. After comparing the changes in SS characteristics of simulated defects with that of the AOEC-tested AUCTs, the change is relatively smaller and therefore it can be concluded that no serious degradation of the AUCT or the adhesive layer has occurred. It was observed that the most critical tests among the AOEC tests are the fluid susceptibility tests, which can cause the biggest change in the SS characteristics. Comparing the performance of the AUCTs bonded with the reference adhesive and the selected TPFs in the AOEC tests, it was seen that some of the TPFs, e.g., Pontacol 22.100 outperforms the reference adhesive, while the other TPFs have similar performance to that of the reference adhesive. Therefore, in conclusion, the AUCTs bonded with the selected TPFs can withstand the operational and environmental conditions of an aircraft structure, and hence, the proposed procedure is easily installed, reparable, and a more reliable method of bonding sensors to aircraft structures.

Curing kinetic of an epoxy resin reinforced with amino-functionalized MWCNTs has been studied by DSC and the obtained results were explained through morphological studies carried out by SEM, TEM, FEG-SEM, and molecular simulation tools. The presence of MWCNTs in the curing reaction induces a retardation effect of curing reaction and a decrease of the reaction heat. Both are associated with the adsorption of curing agent molecules inside carbon nanotubes, which was proved through the application of electron microscopic techniques and molecular simulation tools. It has been also demonstrated that there is a chemical reaction between amine groups anchored to the nanotubes and oxirane rings of epoxy monomer, which improves the nanoreinforcement/matrix interfacial adhesion, appearing a chemical interphase. The glass transition temperature (Tg) of epoxy matrix increases by the addition of MWCNTs due to the restriction of its mobility.

This study involved developing a matrix-type transdermal therapeutic system comprising of ondansetron hydrochloride with 7:3 ratio of hydrophilic and hydrophobic polymeric combinations using solvent evaporation technique. The effects of permeation enhancers were studied at the concentrations of 2.5% and 5% using essential oils such as menthol oil, eucalyptus oil, clove oil, lemon grass oil and the blend of best volatile oil with Tween 20 dibutyl phthalate and glycerin were used as plasticizers. Formulated patches were evaluated for thickness, folding endurance, drug content, percent moisture absorption, percent moisture loss, tensile strength and water vapour transmission rate. There was no physicalchemical incompatibility between the drug and the polymers. The results of in vitro drug release studies showed that the blend of menthol oil and Tween 20 exhibited maximum release. The optimized formulation was found to be stable during the stability studies. The developed transdermal patches increase the efficacy and improve the bioavailability. [ABSTRACT FROM AUTHOR]

Confident identification of pericytes (PCs) remains an obstacle in the field, as a single molecular marker for these unique perivascular cells remains elusive. Adding to this challenge is the recent appreciation that PC populations may be heterogeneous, displaying a range of morphologies within capillary networks. We found additional support on the ultrastructural level for the classification of these PC subtypes-"thin-strand" (TSP), mesh (MP), and ensheathing (EP)-based on distinct morphological characteristics. Interestingly, we also found several examples of another cell type, likely a vascular smooth muscle cell, in a medial layer between endothelial cells (ECs) and pericytes (PCs) harboring characteristics of the ensheathing type. A conserved feature across the different PC subtypes was the presence of extracellular matrix (ECM) surrounding the vascular unit and distributed in between neighboring cells. The thickness of this vascular basement membrane was remarkably consistent depending on its location, but never strayed beyond a range of 150-300 nm unless thinned to facilitate closer proximity of neighboring cells (suggesting direct contact). The density of PC-EC contact points ("peg-and-socket" structures) was another distinguishing feature across the different PC subtypes, as were the apparent contact locations between vascular cells and brain parenchymal cells. In addition to this thinning, the extracellular matrix (ECM) surrounding EPs displayed another unique configuration in the form of extensions that emitted out radially into the surrounding parenchyma. Knowledge of the origin and function of these structures is still emerging, but their appearance suggests the potential for being mechanical elements and/or perhaps signaling nodes via embedded molecular cues. Overall, this unique ultrastructural perspective provides new insights into PC heterogeneity and the presence of medial cells within the microvessel wall, the consideration of extracellular matrix (ECM) coverage as another PC identification criteria, and unique extracellular matrix (ECM) configurations (i.e., radial extensions) that may reveal additional aspects of PC heterogeneity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abdelazim, Payne, Nolan, Paralkar, Bradley, Kanodia, Gude, Ward, Monavarfeshani, Fox and Chappell.)

Background: Vascular pericytes stabilize blood vessels and contribute to their maturation, while playing other key roles in microvascular function. Nevertheless, relatively little is known about involvement of their precursors in the earliest stages of vascular development, specifically during vasculogenesis., Methods: We combined high-power, time-lapse imaging with transcriptional profiling of emerging pericytes and endothelial cells in reporter mouse and cell lines. We also analyzed conditional transgenic animals deficient in Cx43/Gja1 (connexin 43/gap junction alpha-1) expression within Ng2+ cells., Results: A subset of Ng2-DsRed+ cells, likely pericyte/mural cell precursors, arose alongside endothelial cell differentiation and organization and physically engaged vasculogenic endothelium in vivo and in vitro. We found no overlap between this population of differentiating pericyte/mural progenitors and other lineages including hemangiogenic and neuronal/glial cell types. We also observed cell-cell coupling and identified Cx43-based gap junctions contributing to pericyte-endothelial cell precursor communication during vascular assembly. Genetic loss of Cx43/Gja1 in Ng2+ pericyte progenitors compromised embryonic blood vessel formation in a subset of animals, while surviving mutants displayed little-to-no vessel abnormalities, suggesting a resilience to Cx43/Gja1 loss in Ng2+ cells or potential compensation by additional connexin isoforms., Conclusions: Together, our data suggest that a distinct pericyte lineage emerges alongside vasculogenesis and directly communicates with the nascent endothelium via Cx43 during early vessel formation. Cx43/Gja1 loss in pericyte/mural cell progenitors can induce embryonic vessel dysmorphogenesis, but alternate connexin isoforms may be able to compensate. These data provide insight that may reshape the current framework of vascular development and may also inform tissue revascularization/vascularization strategies.

Objective: A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)-induced seizures, and to evaluate the effect of microbial metabolite S-equol on neuronal physiology as well as TMEV-induced neuronal hyperexcitability ex vivo., Methods: We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0-7 days postinfection (dpi). Fecal samples were collected at 5-7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole-cell patch-clamp recordings in cortical neurons to investigate the effect of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability., Results: We demonstrated that gut microbiota diversity is significantly altered in TMEV-infected mice at 5-7 dpi, exhibiting separation in beta diversity in TMEV-infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S-equol-producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S-equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV-infected mice, and exogenous application of microbial-derived S-equol ameliorated this TMEV-induced hyperexcitability., Significance: Our study presents the first evidence of microbial-derived metabolite S-equol as a potential mechanism for alteration of TMEV-induced neuronal excitability. These findings provide new insight for the novel role of S-equol and the gut-brain axis in epilepsy treatment., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Hydrophobicity of PLA nanoparticles makes them a good substrate for macrophageal and reticulo-endothelial system uptake. Long-circulating properties can be imparted to these particles by coating them with hydrophilic stabilizers. Surface-modified PLA nanoparticles loaded with anti-cancer agent temozolomide were fabricated by solvent evaporation method and coated with surface modifiers. Selection of the surface modifier was based upon uptake of nanoparticles by K9 cells (liver cells). The particles were prepared and characterized for various physicochemical properties using transmission electron microscopy, differential scanning calorimetry, powder X-ray diffraction and in vitro dissolution studies. In vitro BBB permeation studies were performed using the co-culture model developed by using Madin-Darby canine kidney and C6 glioma cells as endothelial and glial cells, respectively. In vitro C6 glioma cell cytotoxicity, cellular proliferation, cellular migration and cellular uptake studies due to developed nanoparticles was assessed. In vivo studies such as pharmacokinetics, qualitative and quantitative biodistribution studies were performed for the developed nanoparticles. Drug-loaded nanoparticles with entrapment efficiency of 50% were developed. PEG-1000 and polysorbate-80 coated nanoparticles were least taken up by the liver cells. Characterization of the nanoparticles revealed formation of spherical shape nanoparticles, with no drug and excipient interaction. In vivo pharmacokinetics of developed nanoparticles depicted enhancement of half-life, area under the curve and mean residence time of the drug. Qualitative and quantitative biodistribution studies confirmed enhanced permeation of the drug into the brain upon loading into nanoparticles with less deposition in the highly perfused organs like lung, liver, spleen, heart and kidney.

Nanoparticles are being increasingly used in the field of cancer treatment due to their unique properties and advantages. The aim of the present research work was to prepare and characterize a polymeric albumin nanosystem for Cisplatin and evaluate its in-vitro efficacy against B16F10 melanoma. The developed nanoparticles were almost spherical in shape with a particle size in the range of 150-300 nm, low polydispersity values and about 80% drug entrapment efficiency. Albumin nanocarriers sustained the release of Cisplatin for more than 48 h, suggesting the reduction in dosing schedule for this drug. The results from in-vitro cell line studies indicated the dose dependent cytotoxic potential of drug loaded albumin nanoparticles, their potential to inhibit cell proliferation and induce morphological changes. In addition, these nanoparticles exhibited superiority to Cisplatin in hampering the cell migration. Developed nanoparticles caused cell cycle arrest along with time and concentration dependent cellular uptake in B16F10 cell line. These results signify that the prepared Cisplatin albumin nanoparticles could serve as a promising approach for B16F10 melanoma treatment.

Many patients with suspected allergy are referred to specialist care inappropriately. We aimed to develop and implement an online decision pathway to aid General Practitioners' (GPs) management decisions in suspected allergy. Our study involved 1487 GPs, 3 referral management centres, 5 GP system suppliers, 4 primary care trusts, and 1 specialist allergy clinic. The pathway was implemented by 3/5 GP system suppliers, published to Map of Medicine and on a specialist clinic website. In the first year, the pathway ranked in the top 10/160 local care maps accessed via Map of Medicine and was viewed 900 times. Only 96 GPs registered to use the clinic website. Only 110 (7%) GPs responded to the feedback request, of which 13/110 (12%) had used the pathway; nearly all thought it useful. It was used by referral management centres as explanation of rejected referrals. Alternative approaches to embed its use are required. Significance for public healthOne in three people in the UK are affected by allergies during their lifetime. Early diagnosis and appropriate management can improve quality of life and reduce emergency hospitalisation. However, referring patients to secondary care is costly in terms of time and resources. We developed a pathway algorithm to support General Practitioners' (GPs) allergy management and referral decisions to ensure that all referrals to specialist clinics were appropriate. The study illustrates a real world implementation with lessons for those seeking to improve the primary-secondary care interface, implementing pathways in various formats. In the UK, Map of Medicine seems to be the most used software. We demonstrated the difficulty of reaching GPs to encourage adoption of online decision support and suggest new ways forward by expanding care pathways into more detailed protocols for use directly by patients.

The early signaling events in T cell activation through CD3 receptor include a rapid change in intra cellular free calcium concentration and reorganization of actin cytoskeleton. Phosphatidylinositol 4-kinases (PtdIns 4-kinases) are implicated as key components in these early signaling events. The role of type II PtdIns 4-kinase β in CD3 receptor signaling was investigated with the help of short hairpin RNA sequences. Cross-linking of CD3 receptors on Jurkat T Cells with monoclonal antibodies showed an early increase in type II PtdIns 4-kinase activity and co-localization of type II PtdIns 4-kinase β with CD3 ζ. Transfection of Jurkat T Cells with shRNAs inhibited CD3 receptor mediated type II PtdIns 4-kinase activation with a concomitant reduction in intra cellular calcium release, suggesting a role for type II PtdIns 4-kinase β in CD3 receptor signal transduction. Knock-down of type II PtdIns 4-kinase β with shRNAs also correlated with a decrease in PtdIns 4-kinase activity in cytoskeleton fractions and reduced adhesion to matrigel surfaces. These results indicate that type II PtdIns 4-kinase β is a key component in early T cell activation signaling cascades., (Published by Elsevier Masson SAS.)

Metastasis is a complex process facilitated by the action of several genes. Metastasis associated 1 (MTA1) gene is one such gene which assists the process of metastasis by regulating several molecular targets. MTA1 acts as part of a nucleosome remodelling and histone deacetylation complex, which is involved in transcriptional regulation. Expression of MTA1 has been shown to be closely correlated with aggressiveness in several types of cancers, including breast cancer. In the present study we show that MTA1 regulates SMAD7, a component of Transforming growth factor beta (TGFbeta) signalling. TGFbeta signals are transduced to the nucleus by the Smad family of proteins, which includes Smad7, an inhibitory SMAD, which acts as a negative regulator of TGFbeta. On knockdown of MTA1, SMAD7 expression increases. Treating cells with a histone deacetylase inhibitor also increases SMAD7 expression. MTA1 is recruited to SMAD7 promoter region. SMAD7 inhibits activation of SMAD2 and SMAD3 and we show that the levels of these active SMAD proteins are decreased in cells expressing shRNA against MTA1. We further show that on MTA1 knockdown, the expression of downstream targets of SMAD7 is decreased. MTA1 thus appears to regulate a key inhibitor of TGFbeta signalling, SMAD7. By regulating molecules like SMAD7 MTA1 might assist the process of tumourigenesis and metastasis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Fascin is a globular actin cross-linking protein, which plays a major role in forming parallel actin bundles in cell protrusions and is found to be associated with tumor cell invasion and metastasis in various type of cancers including oral squamous cell carcinoma (OSCC). Previously, we have demonstrated that fascin regulates actin polymerization and thereby promotes cell motility in K8-depleted OSCC cells. In the present study we have investigated the role of fascin in tumor progression of OSCC., Methods: To understand the role of fascin in OSCC development and/or progression, fascin was overexpressed along with vector control in OSCC derived cells AW13516. The phenotype was studied using wound healing, Boyden chamber, cell adhesion, Hanging drop, soft agar and tumorigenicity assays. Further, fascin expression was examined in human OSCC samples (N = 131) using immunohistochemistry and level of its expression was correlated with clinico-pathological parameters of the patients., Results: Fascin overexpression in OSCC derived cells led to significant increase in cell migration, cell invasion and MMP-2 activity. In addition these cells demonstrated increased levels of phosphorylated AKT, ERK1/2 and JNK1/2. Our in vitro results were consistent with correlative studies of fascin expression with the clinico-pathological parameters of the OSCC patients. Fascin expression in OSCC showed statistically significant correlation with increased tumor stage (P = 0.041), increased lymph node metastasis (P = 0.001), less differentiation (P = 0.005), increased recurrence (P = 0.038) and shorter survival (P = 0.004) of the patients., Conclusion: In conclusion, our results indicate that fascin promotes tumor progression and activates AKT and MAPK pathways in OSCC-derived cells. Further, our correlative studies of fascin expression in OSCC with clinico-pathological parameters of the patients indicate that fascin may prove to be useful in prognostication and treatment of OSCC.

Background: Tumor-targeted delivery is a desirable approach to improve therapeutic outcome of anticancer drug due to enhanced efficacy and reduced toxicity., Purpose: The present study was aimed to target laminin receptor over-expressed tumor cells using YIGSR (Tyr-Ile-Gly-Ser-Arg) conjugated etoposide loaded micelles in the treatment of metastasis., Methods: YIGSR conjugated micelles prepared using synthesized carboxyl and methoxy terminated poly(ethylene glycol)-b-poly(ϵ-caprolactone) block copolymers were evaluated for it efficacy against highly metastatic B16F10 cell lines conducting cytotoxicity, colony formation, cell migration, cellular uptake and flow cytometry studies. The in-vivo antimetastatic effect of micelles was evaluated using experimental metastatic model on C57BL/6 mice., Results: YIGSR conjugated micelles of particle size 45.2±3.77 nm and zeta potential of-5.7±1.3 mV demonstrated enhanced cytotoxicity and cellular uptake with significant reduction in colony formation and cell migration activities compared to non-conjugated micelles. Furthermore, a markedly inhibition in lung colony formation was observed with these micelles., Discussion: An enhanced cellular internalization of YIGSR conjugated micelles due to laminin receptor based endocytosis resulted in to higher cytotoxicity as well as antimetastatic effect against highly metastatic B16F10 cells., Conclusion: These studies indicate that YIGSR conjugated nanocarrier can be a promising approach in the treatment of tumor metastasis.

In the present study, poly(ethylene glycol)- b -poly(ε-caprolactone) micelles loaded with etoposide (ETO) were formulated and further conjugated with pentapeptide Glu-Ile-Leu-Asp-Val (EILDV) to target α4β1 integrin receptor overexpressed on metastatic tumor cell. Using a distinct ratio of carboxyl-terminated poly(ethylene glycol)- block -poly(ε-caprolactone) (HOOC-PEG- b -PCL) to methoxy-poly(ethylene glycol)- block -poly(ε-caprolactone (CH 3 O-PEG- b -PCL) polymers, we formulated a series of micellar formulations having different surface densities of EILDV and observed optimum cellular uptake of micelles with 10% EILDV surface density by B16F10 cells. The cytotoxicity of EILDV-conjugated micelles was observed close to 1.5-fold higher than plain ETO after 72 h of drug incubation, demonstrating controlled release of drug inside the cell after enhanced intracellular uptake with the ability to selectively target cancer cells. In addition, EILDV-conjugated micelles inhibited the migration of B16F10 cells effectively compared with plain ETO and non-conjugated micellar formulations when cells were treated with equivalent cytotoxic concentration of the drug, i.e., IC 25 . B16F10 cells treated with EILDV-conjugated micelles showed a significant reduction in the attachment of cells to the substrate-coated plate compared with non-conjugated micellar formulations, implying retention of the biological activity of EILDV after coupling to micelles. Furthermore, the in vivo experimental metastasis assay conducted on C57BL/6 mice demonstrated significant activity of EIDLV-conjugated micelles in the reduction of pulmonary metastatic nodule formation in both pretreatment and post-treatment methods. In conclusion, EIDLV-conjugated micelles showed higher efficacy in the treatment of metastasis and would be a promising approach in the treatment of metastasis.

A rapid high performance liquid chromatographic method has been developed and validated for the estimation of ramipril and telmisartan simultaneously in combined dosage form. A Genesis C18 column having dimensions of 4.6x250 mm and particle size of 5 mum in isocratic mode, with mobile phase containing a mixture of 0.01 M potassium dihydrogen phosphate buffer (adjusted to pH 3.4 using orthophosphoric acid): methanol:acetonitrile (15:15:70 v/v/v) was used. The mobile phase was pumped at a flow rate of 1.0 ml/min and the eluents were monitored at 210 nm. The selected chromatographic conditions were found to effectively separate ramipril (R(t): 3.68 min) and telmisartan (R(t): 4.98 min) having a resolution of 3.84. The method was validated in terms of linearity, accuracy, precision, specificity, limit of detection and limit of quantitation. Linearity for ramipril and telmisartan were found in the range of 3.5-6.5 mug/ml and 28.0-52.0 mug/ml, respectively. The percentage recoveries for ramipril and telmisartan ranged from 99.09-101.64% and 99.45-100.99%, respectively. The limit of detection and the limit of quantitation for ramipril was found to be 0.5 mug/ml and 1.5 mug/ml respectively and for telmisartan was found to be 1.5 mug/ml and 3.0 mug/ml, respectively. The method was found to be robust and can be successfully used to determine the drug content of marketed formulations.

Chemosensitivity of the human colon carcinoma HCT-15 cell line to 4'-epidoxorubicin proved to be 100-fold higher than that of its variant HCT-15 EDR. Confocal scanning microscopy showed significant less drug accumulation in HCT-15 EDR. A 2-fold increase in hsp27 expression was found in HCT-15 EDR, with no alteration in hsp70. The expression of the drug exporter Pgp was similar in both cell lines, despite the lower drug accumulation shown by HCT-15 EDR in respect to HCT-15. Other molecules implicated in the acquisition of enhanced chemoresistance or a more active Pgp variant present in HCT-15 EDR, could explain the phenomenon.

Objective: To adapt the telephone interview for cognitive status using the Mini Mental Status Examination as criterium validity, replicating the original development of the test., Design: A quasi-experimental study with independent groups, and a correlational study between both tests and test-retest. SITE. Granada City., Participants: 62 Older population in chronic attention programs of Health Center 15 of them with dementia diagnosis., Measurements and Main Results: Significant statistical differences were found in test scores for dementia patients group, a mild criterium validity (0.65), a high feasibility (0.83) and sensibility (0.77) and a mild specificity (0.60). A significant statistical difference was found between Spanish and USA control groups scores., Conclusions: The adaptation of the test was done and it seems an useful test in dementia studies but is necessary to replicate and more studies about the test.

Family doctors vary in the range of services they provide for their patients. Of 267 practices in Devon and Cornwall, 245 responded to a questionnaire sent in September 1989 asking for information about services to patients. Most doctors consulted at six to eight patients per hour, whether or not an appointment system operated. About two-thirds of patients had access to a female GP. Nine out of ten practices employed a practice nurse. Almost all offered a surgery on Saturday mornings. Most surgeries took the phone over at 8.30 a.m. in the week and started consulting at 9 a.m. Almost half were consulting until 6.30 p.m. or later on at least one day per week. 80% of practices were offering a non-urgent appointment on the same or next day. All practices offered childhood immunisation. 80% offered some form of personal list system. 80% offered minor operations, one-third manipulations, 10% homeopathy, 6% hypnosis and 5% acupuncture.