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This paper presents a modeling process, using the 2D Flux software and an optimization process, based on the Response Surface Method, Central Composite Design, from the Minitab Statistical Software. In this paper, the induction heating in volume of a semi-finished product has been modeled, neglecting the end effect.

In this work, Flux 2D software has been used. It has been coupled with an experimental design method, in order to model the induction heating in volume of a half-finished product, neglecting end effects.

The purpose of this optimization is the identification of optimal parameters for processing the workpiece (the OLC45 steel bar), using inductive heating in volume. Flux 9.3.2 software, in 2D plan, has been employed in order to perform numerical simulations, while Minitab software has been used to determine optimal parameters.

Alcohol/binge drinking among university students has become a major public health problem. Many of young students will be exposed to substantial changes in living arrangements, socialization groups and social activities during the transitional period.

Cardboard packaging is widely used in the food industry, especially as secondary or tertiary packaging, or as transport packaging. In most cases, these packs may contain certain chemical contaminants that can be accidentally transferred to packaged foods. These contaminants include Bisphenol A (BPA) and Formaldehyde, which can cause significant adverse effects, especially to vulnerable persons. For this reason, the purpose of this study was to analyze by a UV - VIS spectrophotometric method the content of BPA and Formaldehyde from 17 corrugated board samples from Romanian producers. BPA concentrations varied between 0.044 mg/dm2 and 0.090 mg/dm2, while Formaldehyde concentrations were lower than 0.048 mg/dm2. The results were compared with the legislation in force to establish their compliance for contact with food.

This paper describes the coupling between the numerical modeling of the induction heating process, using a Matlab-PDE software development, with a statistical model, which uses the Design of Experiments (DOE) concept, based on the Minitab-Full Factorial software, offering optimal solutions as regards the inductive electrothermal equipment.

This paper deals with 3D numerical models of transverse flux inductor with a flexible electromagnetic configuration developed in Flux3D software. The simplified 3D model is coupled with a simplex optimization algorithm in order to attain a maximum uniformity of the transversal profile of power developed within the metallic sheet. The complex 3D model is used for a thoroughly analysis of device.

The paper presents the study and design of a fuse based on a numerical model for the coupling of the electric conduction regime and the transient thermal one. Temperature depending properties and the thermal transfer were considered. Parametrized numerical studies were performed in order to established the time-current curve of the fuse.

The paper presents 2D and 3D models for the study of electromagnetic shielding of a coil. The magnetic fields are computed for defining the shielding effectiveness. Parametrized numerical studies were performed in order to established the influence of shield thickness and height on magnetic field in certain points located in the exterior of coil – shield setup and on induced power within the shield.

There is a critical need for safer and better-tolerated alternatives to address the current limitations of antidepressant treatments for major depressive disorder. Recently, drugs targeting the GABA system via α5-containing GABA A receptors (α5-GABA A R) as negative allosteric modulators (α5-NAMs) have shown promise in alleviating stress-related behaviors in preclinical studies, suggesting that α5-NAMs may have translational relevance as novel antidepressant medications. Here, we evaluated the efficacy of Basmisanil, an α5-NAM that has been evaluated in Phase 2 clinical studies as a cognitive enhancer, in a battery of behavioral tests relevant to coping strategies, motivation, and aversion in male mice, along with plasma and brain pharmacokinetic measurements. Our findings reveal that Basmisanil induces dose-dependent rapid antidepressant-like responses in the forced swim test and sucrose splash test without promoting locomotor stimulating effects. Furthermore, Basmisanil elicits sustained behavioral responses in the female urine sniffing test and sucrose splash test, observed 24 h and 48 h post-treatment, respectively. Bioanalysis of plasma and brain samples confirms effective blood-brain barrier penetration by Basmisanil and extrapolation to previously published data suggest that effects were observed at doses (10 and 30 mg/kg i.p.) corresponding to relatively modest levels of α5-GABA A R occupancy (40-65 %). These results suggest that Basmisanil exhibits a combination of rapid and sustained antidepressant-like effects highlighting the potential of α5-NAMs as a novel therapeutic strategy for depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7 - 33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33 , which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.

Background: Multiple cognitive and psychiatric disorders are associated with an increased tonic inhibitory conductance that is generated by α5 subunit-containing γ-aminobutyric acid type A (α5 GABA A ) receptors. Negative allosteric modulators that inhibit α5 GABA A receptors (α5-NAMs) are being developed as treatments for these disorders. The effects of α5-NAMs have been studied on recombinant GABA A receptors expressed in non-neuronal cells; however, no study has compared drug effects on the tonic conductance generated by native GABA A receptors in neurones, which was the goal of this study., Methods: The effects of five α5-NAMs (basmisanil, Ono-160, L-655,708, α5IA, and MRK-016) on tonic current evoked by a low concentration of GABA were studied using whole-cell recordings in cultured mouse hippocampal neurones. Drug effects on current evoked by a saturating concentration of GABA and on miniature inhibitory postsynaptic currents (mIPSCs) were also examined., Results: The α5-NAMs caused a concentration-dependent decrease in tonic current. The potencies varied as the inhibitory concentration for 50% inhibition (IC 50 ) of basmisanil (127 nM) was significantly higher than those of the other compounds (0.4-0.8 nM). In contrast, the maximal efficacies of the drugs were similar (35.5-51.3% inhibition). The α5-NAMs did not modify current evoked by a saturating GABA concentration or mIPSCs., Conclusions: Basmisanil was markedly less potent than the other α5-NAMs, an unexpected result based on studies of recombinant α5 GABA A receptors. Studying the effects of α5 GABA A receptor-selective drugs on the tonic inhibitory current in neurones could inform the selection of compounds for future clinical trials., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

TOKs are outwardly rectifying K + channels in fungi with two pore-loops and eight transmembrane spans. Here, we describe the TOKs from four pathogens that cause the majority of life-threatening fungal infections in humans. These TOKs pass large currents only in the outward direction like the canonical isolate from Saccharomyces cerevisiae (ScTOK), and distinct from other K + channels. ScTOK, AfTOK1 (Aspergillus fumigatus), and H99TOK (Cryptococcus neoformans grubii) are K + -selective and pass current above the K + reversal potential. CaTOK (Candida albicans) and CnTOK (Cryptococcus neoformans neoformans) pass both K + and Na + and conduct above a reversal potential reflecting the mixed permeability of their selectivity filter. Mutations in CaTOK and ScTOK at sites homologous to those that open the internal gates in classical K + channels are shown to produce inward TOK currents. A favored model for outward rectification is proposed whereby the reversal potential determines ion occupancy, and thus, conductivity, of the selectivity filter gate that is coupled to an imperfectly restrictive internal gate, permitting the filter to sample ion concentrations on both sides of the membrane., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Studying herbal products derived from local and traditional knowledge and their value chains is one of the main challenges in ethnopharmacology. The majority of these products have a long history of use, but non-harmonized trade and differences in regulatory policies between countries impact their value chains and lead to concerns over product efficacy, safety and quality. Veronica officinalis L. (common speedwell), a member of Plantaginaceae family, has a long history of use in European traditional medicine, mainly in central eastern Europe and the Balkans. However, no specified control tests are available either to establish the quality of derived herbal products or for the discrimination of its most common substitute, V. chamaedrys L. (germander speedwell). In this study, we use DNA metabarcoding and high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) to authenticate sixteen V. officinalis herbal products and compare the potential of the two approaches to detect substitution, adulteration and the use of unreported constituents. HPLC-MS showed high resolution in detecting phytochemical target compounds, but did not enable detection of specific plant species in the products. DNA metabarcoding detected V. officinalis in only 15% of the products, whereas it detected V. chamaedrys in 62% of the products. The results confirm that DNA metabarcoding can be used to test for the presence of Veronica species, and detect substitution and/or admixture of other Veronica species, as well as simultaneously detect all other species present. Our results confirm that none of the herbal products contained exactly the species listed on the label, and all included substitutes, contaminants or fillers. This study highlights the need for authentication of raw herbals along the value chain of these products. An integrative methodology can assess both the quality of herbal products in terms of target compound concentrations and species composition, as well as admixture and substitution with other chemical compounds and plants.

Valvular disease is a frequent cardiac pathology leading to heart failure and, ultimately, death. Mitral regurgitation, defined as the inability of the two mitral leaflets to coapt, is a common valvular disease and a self sustained pathology. A better understanding of the mitral valve histological layers provides a better understanding of the leaflet and chordae changes in mitral valve prolapse. Mitral valve prolapse may occur in myxomatous degenerative abnormalities, connective tissue disorders or in sporadic isolated cases. It is the most common mitral abnormality of non-ischemic cause leading to severe surgery-requiring mitral regurgitation. In addition to standard echocardiographic investigations, newly implemented three-dimensional techniques are being used and they permit a better visualisation, from the so-called 'surgical view', and an improved evaluation of the mitral valve. Hypertrophic cardiomyopathy is the most frequent inherited myocardial disease caused by mutations in various genes encoding proteins of the cardiac sarcomere, leading to a marked left ventricular hypertrophy unexplained by other comorbidities. The pathological echocardiographic hallmarks of hypertrophic cardiomyopathy are left ventricular hypertrophy, left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. The systolic anterior motion of the mitral valve contributes to the development of mitral regurgitation and further narrows the left ventricular outflow tract, leading to more severe symptomatology. Cardiac magnetic resonance imaging accurately measures the left ventricular mass, the degree of diastolic function and it may also be used to distinguish phenotypic variants. The clinical outcome of patients with these pathologies is mostly determined by the selected option of treatment. The purpose of surgical correction regarding mitral valve involvement is to restore valvular competence. Surgery has proven to be the only useful treatment in preventing heart failure, improving symptomatology and reducing mortality. Our approach wishes to enhance the understanding of the mitral valve's involvement in hypertrophic cardiomyopathy and mitral valve prolapse from genetic, haemodynamic and clinical perspectives, as well as to present novelties in the grand field of treatment., Competing Interests: Conflict of interests: The authors declare no conflicts of interest., (Copyright: © 2016, Popa et al. and Applied Systems.)

The calcium-activated chloride channel ANO1 regulates multiple physiological processes. However, little is known about the mechanism of channel gating and regulation of ANO1 activity. Using a high-throughput, random mutagenesis-based variomics screen, we generated and functionally characterized ∼6000 ANO1 mutants and identified novel mutations that affected channel activity, intracellular trafficking, or localization of ANO1. Mutations such as S741T increased ANO1 calcium sensitivity and rendered ANO1 calcium gating voltage-independent, demonstrating a critical role of the re-entrant loop in coupling calcium and voltage sensitivity of ANO1 and hence in regulating ANO1 activation. Our data present the first unbiased and comprehensive study of the structure-function relationship of ANO1. The novel ANO1 mutants reported have diverse functional characteristics, providing new tools to study ANO1 function in biological systems, paving the path for a better understanding of the function of ANO1 and its role in health and diseases., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary inflammation with increased numbers of macrophages located in the parenchyma. These macrophages have the capacity to mediate the underlying pathophysiology of COPD; therefore, a better understanding of their function in chronic inflammation associated with this disease is vital. Ion channels regulate many cellular functions; however, their role in macrophages is unclear. This study examined the expression and function of transient receptor potential (TRP) channels in human macrophages. Human alveolar macrophages and lung tissue macrophages expressed increased mRNA and protein for TRPC6 when compared with monocytes and monocyte-derived macrophages. Moreover, TRPC6 mRNA expression was significantly elevated in alveolar macrophages from patients with COPD compared with control subjects. There were no differences in mRNA for TRPC3 or TRPC7. Although mRNA for TRPM2 and TRPV1 was detected in these cells, protein expression could not be determined. Fractionation of lung-derived macrophages demonstrated that TRPC6 protein was more highly expressed by smaller macrophages compared with larger macrophages. Using whole-cell patch clamp electrophysiology, TRPC6-like currents were measured in both macrophage subpopulations with appropriate biophysical and basic pharmacological profiles. These currents were active under basal conditions in the small macrophages. These data suggest that TRPC6-like channels are functional on human lung macrophages, and may be associated with COPD.

Voltage-gated Na(+) channels play a fundamental role in the excitability of nerve and muscle cells. Defects in fast Na(+) channel inactivation can cause hereditary muscle diseases with hyper- or hypoexcitability of the sarcolemma. To explore the kinetics and gating mechanisms of noninactivating muscle Na(+) channels on a molecular level, we analyzed single channel currents from wild-type and five mutant Na(+) channels. The mutations were localized in different protein regions which have been previously shown to be important for fast inactivation (D3-D4-linker, D3/S4-S5, D4/S4-S5, D4/S6) and exhibited distinct grades of defective fast inactivation with varying levels of persistent Na(+) currents caused by late channel reopenings. Different gating schemes were fitted to the data using hidden Markov models with a correction for time interval omission and compared statistically. For all investigated channels including the wild-type, two open states were necessary to describe our data. Whereas one inactivated state was sufficient to fit the single channel behavior of wild-type channels, modeling the mutants with impaired fast inactivation revealed evidence for several inactivated states. We propose a single gating scheme with two open and three inactivated states to describe the behavior of all five examined mutants. This scheme provides a biological interpretation of the collected data, based on previous investigations in voltage-gated Na(+) and K(+) channels.

The formation of disulfide bridges is a classical approach used to study the mobility, proximity and distances of residues in a variety of proteins, including ligand- and voltage-gated ion channels. We performed patch-clamp studies to investigate the interaction of a pair of cysteines introduced into the human skeletal muscle voltage-gated Na+ channel (hNa(v)1.4) using the oxidation catalyst, Cu2+ (1,10-phenanthroline)3 (CuPhen). Our experiments resulted in a surprising finding, a reversible current inhibition of the mutant I1160C/L1482C containing two cysteines in the D3/and D4/S4-S5 loops, subjected to oxidative cross-linking in the presence of CuPhen. We report here that CuPhen is an open channel blocker of both mutant and wild-type (WT) hNa(v)1.4 channels, however, for WT channels a more than 10-fold higher concentration was needed to induce the same effect. Moreover, 1,10-phenanthroline was capable of blocking Na+ channels in the absence of Cu2+ ions. Our results indicate a use- and voltage-dependent binding and unbinding of CuPhen, reminiscent of the lidocaine quaternary derivative QX-314 and the neurotoxin batrachotoxin. Care should be taken when using CuPhen as an oxidizing reagent in cross-linking experiments, since it may directly affect channel activity. Our results identify CuPhen (and phenantroline) as a novel use-dependent inhibitor of Na+ channels, a mechanism that is shared by drugs widely used in the treatment of epilepsy, neuropathic pain, cardiac arrhythmia and myotonia. We hypothesize that I1160C in D3/S4-S5 and the corresponding L1482C mutation in D4/S4-S5 could allosterically affect a binding site located in the inner pore region of the channel.

Single ion channel currents can be analysed by hidden or aggregated Markov models. A classical result from Fredkin et al. (Proceedings of the Berkeley conference in honor of Jerzy Neyman and Jack Kiefer, vol I, pp 269-289, 1985) states that the maximum number of identifiable parameters is bounded by 2n(o)n(c), where n(o) and n(c) denote the number of open and closed states, respectively. We show that this bound can be overcome when the probabilities of the initial distribution are known and the data consist of several sweeps.

Cytoplasmic S4-S5 loops have been shown to be involved in fast inactivation of voltage-gated ion channels. We studied mutations in these loops and their potential cooperative effects in domains D3 (N1151C, A1152C, I1160C/A) and D4 (F1473C, L1482C/A) of the human skeletal muscle Na(+) channel alpha-subunit (hNa(v)1.4) using expression in tsA201 cells and the whole cell patch-clamp technique. All cysteine mutations were accessible to intracellularly applied sulfhydryl reagents which considerably destabilized fast inactivation. For different combinations of corresponding D3/D4 double mutations, fast inactivation could be almost completely removed. Thermodynamic cycle analysis indicated an additive effect for N1151C/F1473C and a significant cooperative effect for I1160/L1482 double mutations. Application of oxidizing reagents such as Cu-phenanthroline to link two cysteines via a disulfide bridge did not reveal evidence for a direct physical interaction of cysteines in D3 and D4. In addition to the pronounced alterations of fast inactivation, mutations of I1160 shifted steady-state activation in the hyperpolarizing direction and slowed the kinetics of both activation and deactivation. Sulfhydryl reagents had charge-dependent effects on I1160C suggesting interaction with negative charges in another protein region. We conclude that fast inactivation of the Na(+) channel involves both S4-S5 loops in D3 and D4 in a cooperative manner. D3/S4-S5 also plays an important role in activation and deactivation.

Clonogenic neural stem cells (NSCs) are self-renewing cells that maintain the capacity to differentiate into brain-specific cell types, and may also replace or repair diseased brain tissue. NSCs can be directly isolated from fetal or adult nervous tissue, or derived from embryonic stem cells. Here, we describe the efficient conversion of human adult bone marrow stromal cells (hMSC) into a neural stem cell-like population (hmNSC, for human marrow-derived NSC-like cells). These cells grow in neurosphere-like structures, express high levels of early neuroectodermal markers, such as the proneural genes NeuroD1, Neurog2, MSl1 as well as otx1 and nestin, but lose the characteristics of mesodermal stromal cells. In the presence of selected growth factors, hmNSCs can be differentiated into the three main neural phenotypes: astroglia, oligodendroglia and neurons. Clonal analysis demonstrates that individual hmNSCs are multipotent and retain the capacity to generate both glia and neurons. Our cell culture system provides a powerful tool for investigating the molecular mechanisms of neural differentiation in adult human NSCs. hmNSCs may therefore ultimately help to treat acute and chronic neurodegenerative diseases.