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Variants in SLC26A4 (pendrin) are the most common reasons for genetic hearing loss and vestibular dysfunction in East Asians. In patients with Pendred syndrome and DFNB4 (autosomal recessive type of genetic hearing loss 4), caused by variants in SLC26A4, the hearing function is residual at birth and deteriorates over several years, with no curative treatment for these disorders. In the present study, we revealed that a novel small molecule restores the expression and function of mutant pendrin. High-throughput screening of 54,000 small molecules was performed. We observed that pendrin corrector (PC2–1) increased the surface expression and anion exchange activity of p.H723R pendrin (H723R-PDS), the most prevalent genetic variant that causes Pendred syndrome and DFNB4. Furthermore, in endogenous H723R-PDS-expressing human nasal epithelial cells, PC2–1 significantly increased the surface expression of pendrin. PC2–1 exhibited high membrane permeability in vitro and high micromolar concentrations in the cochlear perilymph in vivo. In addition, neither inhibition of Kv11.1 activity in the human ether-a-go-go-related gene assay nor cell toxicity in the cell proliferation assay was observed at a high PC2–1 concentration (30 μM). These preclinical data support the hypothesis of the druggability of mutant pendrin using the novel corrector molecule PC2–1. In conclusion, PC2–1 may be a new therapeutic molecule for ameliorating hearing loss and treating vestibular disorders in patients with Pendred syndrome or DFNB4.

Background and AimCystic fibrosis (CF) is a genetic disease that is difficult to treat and caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have been used to treat the symptom caused by CFTR mutations by restoring CFTR protein function. However, the data on children with CF are scarce. This meta-analysis aimed to evaluate the effectiveness and safety of this therapy in children diagnosed with CF.Materials and MethodsRelevant studies were identified through searching medical databases before April 1, 2022. The primary outcomes of ppFEV1, lung clearance index2.5 (LCI2.5), sweat chloride concentration (SwCI), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were nutritional status (weight, BMI, stature, and their z-score) and adverse events under therapy.ResultsA total of twelve studies were included. Compared with the placebo group, the pooled outcome of the ppFEV1, LCI2.5, SwCI, and CFQ-R score were improved by 7.91 {[95% confidence interval (CI), 3.71–12.12], –1.00 (95% CI, –1.38 to –0.63), –35.22 (95% CI, –55.51 to –14.92), and 4.45 (95% CI, 2.31–6.59), respectively}. Compared with the placebo group, the pooled result of the change in weight was improved by 1.53 (95% CI, 0.42–2.63). All the aforementioned results were also improved in single-arm studies. No clear differences in adverse events were found between CFTR modulator therapy and the placebo group.ConclusionCFTR modulators could improve multiaspect function in children with CF and result in comparable adverse events.

The problem of converting attenuated hydraulic energy into power energy in an artificial local resistance unit placed on a gravity drinking water pipeline (outlet control valve, pressure regulator) without disrupting the hydraulic regime of the water pipeline is examined. It is recommended to replace the regulator with the same resistance hydraulic turbine, and thus, with its corrective device, automatically adjust the consumption outlet of the water pipe. The energy and economic data of the hydraulic turbine unit to be built on the «Arzakan-Yerevan» drinking water main pipelines have been presented as an example of proposal implementation. According to estimations, the small hydroelectric power plant on the Yerevan water pipeline could produce 90 million kWh of electricity per year. It should be noted that the water supply system in Yerevan has around 300 half-open valves and pressure control devices, and in case of conversion of many of them, it is possible to apply the suggestion given in the article.

Background: Cystic fibrosis is a rare, recessive, progressive genetic disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have recently been developed to treat the molecular consequences of CFTR mutations and restore CFTR protein function. However, the data on triple combination therapy (mainly from Vertex Pharmaceuticals, which is most tested in clinical trials) are limited. This meta-analysis was aimed to assess the efficacy and safety of this therapy according to different mutation genotypes and comparators. Methods: Relevant publications were identified through searching several medical databases before 31 December 2021. The primary outcomes of ppFEV1, sweat chloride concentration and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were adverse events in triple combination therapy. Results: Six randomized controlled trials were eligible for analysis. The total outcome of the ppFEV1 change was higher with triple combination therapy than triple placebo or active control (mean difference, MD, 13.6% and 8.74%, respectively). The pooled result of sweat chloride concentrations with triple combination therapy was lower than that of triple placebo or active control (MD, −44.13 and −39.26, respectively). The pooled estimate of the CFQ-R score was higher with triple combination therapy than triple placebo or active control (MD, 19.8% and 14.63%, respectively). No clear differences in adverse events were found between triple combination therapy and the control (placebo or active control). Conclusion: CFTR modulators in triple combination achieve better clinical results than placebo and active control, and result in comparable adverse events. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display%5frecord.php?ID=CRD42021293402, identifier PROSPERO 2021 CRD42021293402. [ABSTRACT FROM AUTHOR]

The presence in the Celestina of terms with changing semantical value along the centuries, such as auctor, autor (Italian auctore, autore), imprimir, imprimidor, impresor and corrector, has posed a big obstacle in order to understand the creational process of this work, as well as the dates of its first editions and some notions about its authorship. Through a thorough analysis of these concepts and their implications this paper validates some of the most recent researches about the mentioned points.

Background: Cystic fibrosis is a rare, recessive, progressive genetic disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have recently been developed to treat the molecular consequences of CFTR mutations and restore CFTR protein function. However, the data on triple combination therapy (mainly from Vertex Pharmaceuticals, which is most tested in clinical trials) are limited. This meta-analysis was aimed to assess the efficacy and safety of this therapy according to different mutation genotypes and comparators.Methods: Relevant publications were identified through searching several medical databases before 31 December 2021. The primary outcomes of ppFEV1, sweat chloride concentration and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were adverse events in triple combination therapy.Results: Six randomized controlled trials were eligible for analysis. The total outcome of the ppFEV1 change was higher with triple combination therapy than triple placebo or active control (mean difference, MD, 13.6% and 8.74%, respectively). The pooled result of sweat chloride concentrations with triple combination therapy was lower than that of triple placebo or active control (MD, −44.13 and −39.26, respectively). The pooled estimate of the CFQ-R score was higher with triple combination therapy than triple placebo or active control (MD, 19.8% and 14.63%, respectively). No clear differences in adverse events were found between triple combination therapy and the control (placebo or active control).Conclusion: CFTR modulators in triple combination achieve better clinical results than placebo and active control, and result in comparable adverse events.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021293402, identifier PROSPERO 2021 CRD42021293402.

We prove homogenization for a class of viscous Hamilton-Jacobi equations in the stationary & ergodic setting in one space dimension. Our assumptions include most notably the following: the Hamiltonian is of the form G (p) + β V (x , ω) , the function G is coercive and strictly quasiconvex, min ⁡ G = 0 , β > 0 , the random potential V takes values in [ 0 , 1 ] with full support and it satisfies a hill condition that involves the diffusion coefficient. Our approach is based on showing that, for every direction outside of a bounded interval (θ 1 (β) , θ 2 (β)) , there is a unique sublinear corrector with certain properties. We obtain a formula for the effective Hamiltonian and deduce that it is coercive, identically equal to β on (θ 1 (β) , θ 2 (β)) , and strictly monotone elsewhere. [ABSTRACT FROM AUTHOR]

Alignment system, with large stroke, high accuracy, and deviation automatic correction properties, is really attractive for performing the task of wafer-level flip-chip packaging. The motivation for this work is enabling a common packaging system to run in a manner of deviation automatic correction. To this end, in this article, three parallel kinematic flexure limbs with lever displacement amplifier are designed to construct a 3-RRR (R is revolute) XY θ deviation corrector. After a series of kinematics theoretic analyses and dimension optimizations, the mechanism is evaluated. Given the dynamic coupling linear and angular motion of the corrector are hard to be acquired simultaneously by common commercial displacement sensors, a “coarse-precise” composite visual inspection algorithm is designed to capture the precise motion in XY θ directions at the same time. Then, a series of validation experiments are successfully carried out, including visual inspection test, kinematics characterization, open-loop and closed-loop tracking tests, and flip-chip deviation correction test. The results indicate that the resolution and the absolute positioning accuracy of the developed alignment system are achieved up to 40 nm/10 μrad and 0.3  μm/30  μrad, respectively, and the positioning period under maximum range is kept within two control cycles (0.7 s). Finally, in association with the deviation corrector, the accuracy of the alignment system is improved up to 0.3  μm/0.03 mrad, which proved that the proposed strategy provides an effective solution for the one-step accurate alignment operation of advanced chip packaging. [ABSTRACT FROM AUTHOR]

Cystic fibrosis is the most common life-shortening genetic disease affecting Caucasians, clinically manifested by fat malabsorption, poor growth and nutrition, and recurrent sinopulmonary infections. Newborn screening programs for cystic fibrosis are now implemented throughout the United States and in many nations worldwide. Early diagnosis and interventions have led to improved clinical outcomes for people with cystic fibrosis. Newer cystic fibrosis transmembrane conductance regulator potentiators and correctors with mutation-specific effects have increasingly been used in children, and these agents are revolutionizing care. Indeed, it is possible that highly effective modulator therapy used early in life could profoundly affect the trajectory of cystic fibrosis lung disease, and primary prevention may be achievable.

Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity. Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition. Traditionally, CF has been symptomatically managed, but over the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor. To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources. [ABSTRACT FROM AUTHOR]

Variants in SLC26A4 (pendrin) are the most common reasons for genetic hearing loss and vestibular dysfunction in East Asians. In patients with Pendred syndrome and DFNB4 (autosomal recessive type of genetic hearing loss 4), caused by variants in SLC26A4 , the hearing function is residual at birth and deteriorates over several years, with no curative treatment for these disorders. In the present study, we revealed that a novel small molecule restores the expression and function of mutant pendrin. High-throughput screening of 54,000 small molecules was performed. We observed that pendrin corrector (PC2–1) increased the surface expression and anion exchange activity of p.H723R pendrin (H723R-PDS), the most prevalent genetic variant that causes Pendred syndrome and DFNB4. Furthermore, in endogenous H723R-PDS-expressing human nasal epithelial cells, PC2–1 significantly increased the surface expression of pendrin. PC2–1 exhibited high membrane permeability in vitro and high micromolar concentrations in the cochlear perilymph in vivo. In addition, neither inhibition of Kv11.1 activity in the human ether-a-go-go-related gene assay nor cell toxicity in the cell proliferation assay was observed at a high PC2–1 concentration (30 μM). These preclinical data support the hypothesis of the druggability of mutant pendrin using the novel corrector molecule PC2–1. In conclusion, PC2–1 may be a new therapeutic molecule for ameliorating hearing loss and treating vestibular disorders in patients with Pendred syndrome or DFNB4. [ABSTRACT FROM AUTHOR]

The aim of the article is the presentation of the authors’ approach to pedagogical work differentiation based on educational activities of teachers at school of the future. The results of starkly new teacher training system implementation in pedagogical higher schools as part of an innovative strategic project "The teacher of the future" are introduced. The content and technology of students’ training in accordance with new teaching specialties are in the focus. The model of pedagogical work differentiation and the corresponding system of future teachers training provides a number of advantages and the solution of key problems in the school system in Russia. It allows to: 1) make the system of teacher education significantly more open due to closer cooperation with school through the educational process at all levels; 2) to increase the prestige of the teaching profession, to provide a more flexible and mobile training methods for it; 3) to create the conditions for career prospects within the teaching profession; 4) to carry out the practical orientation of the teacher training from the earliest training stages, to make this process a particular school oriented; 5) to provide training according to the new paradigm of working school teachers who are ready to change and improve the quality of their teaching.

The growing role of S&T funds as one of the important mechanisms for financing science results in necessity to improve methods for evaluating and planning activities of such funds. In this paper we identified some indicators of scientific activity based on statistical data analysis. On our opinion these indicators should be taken into account for evaluation and planning of R&D activities, in particular, regarding S&T funds. One of the key indicator, which determines pace of scientific development is GERD per one researcher. Accelerated development of science, which manifests itself in a significant increase in its effectiveness. At the same time, it is sufficient to keep the magnitude in order to achieve high values of performance and efficiency of scientific activity if management of financial flows is enough efficient. If each researcher publishes approximately 1 work in 2 years, it will be enough to ensure the quality and relevance of scientific publications.

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. Different mutations involving the cystic fibrosis transmembrane regulator protein (CFTR) gene, which encodes the CFTR channel, are involved in CF. A number of life-prolonging therapies have been conceived and deeply investigated to combat this disease. Among them, the administration of the so-called CFTR modulators, such as correctors and potentiators, have led to quite beneficial effects. Recently, based on QSAR (quantitative structure activity relationship) studies, we reported the rational design and synthesis of compound 2, an aminoarylthiazole-VX-809 hybrid derivative exhibiting promising F508del-CFTR corrector ability. Herein, we explored the docking mode of the prototype VX-809 as well as of the aforementioned correctors in order to derive useful guidelines for the rational design of further analogues. In addition, we refined our previous QSAR analysis taking into account our first series of in-house hybrids. This allowed us to optimize the QSAR model based on the chemical structure and the potency profile of hybrids as F508del-CFTR correctors, identifying novel molecular descriptors explaining the SAR of the dataset. This study is expected to speed up the discovery process of novel potent CFTR modulators.

Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report that variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry multiplexed with isobaric tandem mass tags was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knockdowns sensitize P67L to VX-445 and further enhance the trafficking correction of this variant. Partial inhibition of protein translation also mildly sensitizes P67L CFTR to VX-445 correction, supporting a role for translational dynamics in the rescue mechanism of VX-445. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize nonresponsive CFTR variants to known and available correctors., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We study continuous-time (variable speed) random walks in random environments on Z d , d ≥ 2 , where, at time t , the walk at x jumps across edge ( x , y ) at time-dependent rate a t ( x , y ) . The rates, which we assume stationary and ergodic with respect to space–time shifts, are symmetric and bounded but possibly degenerate in the sense that the total jump rate from a vertex may vanish over finite intervals of time. We formulate conditions on the environment under which the law of diffusively-scaled random walk path tends to Brownian motion for almost every sample of the rates. The proofs invoke Moser iteration to prove sublinearity of the corrector in pointwise sense; a key additional input is a conversion of certain weighted energy norms to ordinary ones. Our conclusions apply to random walks on dynamical bond percolation and interacting particle systems as well as to random walks arising from the Helffer–Sjöstrand representation of gradient models with certain non-strictly convex potentials. [ABSTRACT FROM AUTHOR]

We present an introduction to periodic and stochastic homogenization of elliptic partial differential equations. The first part is concerned with the qualitative theory, which we present for equations with periodic and random coefficients in a unified approach based on Tartar's method of oscillating test functions. In particular, we present a self-contained and elementary argument for the construction of the sublinear corrector of stochastic homogenization. (The argument also applies to elliptic systems and in particular to linear elasticity). In the second part we briefly discuss the representation of the homogenization error by means of a two-scale expansion. In the last part we discuss some results of quantitative stochastic homogenization in a discrete setting. In particular, we discuss the quantification of ergodicity via concentration inequalities, and we illustrate that the latter in combination with elliptic regularity theory leads to a quantification of the growth of the sublinear corrector and the homogenization error. [ABSTRACT FROM AUTHOR]

To reduce cost, increase resolution, and reduce errors due to changing light intensity of the VIS SPEC, a new technique is proposed which applies the Kalman algorithm along with a simple hardware setup and implementation. In real time, the SPEC automatically corrects spectral data errors resulting from an unstable light source by adding a photodiode sensor to monitor the changes in light source intensity. The Kalman algorithm is applied on the data to correct the errors. The light intensity instability is one of the sources of error considered in this work. The change in light intensity is due to the remaining lifetime, working time and physical mechanism of the halogen lamp, and/or battery and regulator stability. Coefficients and parameters for the processing are determined from MATLAB simulations based on two real types of datasets, which are mono-changing and multi-changing datasets, collected from the prototype SPEC. From the saved datasets, and based on the Kalman algorithm and other computer algorithms such as divide-and-conquer algorithm and greedy technique, the simulation program implements the search for process noise covariance, the correction function and its correction coefficients. These components, which will be implemented in the processor of the SPEC, Kalman algorithm and the light-source-monitoring sensor are essential to build the Kalman corrector. Through experimental results, the corrector can reduce the total error in the spectra on the order of 10 times; for certain typical local spectral data, it can reduce the error by up to 60 times. The experimental results prove that accuracy of the SPEC increases considerably by using the proposed Kalman corrector in the case of changes in light source intensity. The proposed Kalman technique can be applied to other applications to correct the errors due to slow changes in certain system components. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is caused by mutations that compromise the expression and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Most people with CF harbor a common misfolded variant (ΔF508) that can be partially rescued by therapeutic "correctors" that restore its expression. Nevertheless, many other CF variants are insensitive to correctors. Using deep mutational scanning, we quantitatively compare the effects of two correctors on the plasma membrane expression of 129 CF variants. Though structural calculations suggest corrector binding provides similar stabilization to most variants, it's those with intermediate expression and mutations near corrector binding pockets that exhibit the greatest response. Deviations in sensitivity appear to depend on the degree of variant destabilization and the timing of misassembly. Combining correctors appears to rescue more variants by doubling the binding energy and stabilizing distinct cotranslational folding transitions. These results provide an overview of rare CF variant expression and establish new tools for precision pharmacology. [Display omitted] • The PME of CF variants is profiled by DMS • The variant-specific effects of two approved correctors are quantitatively mapped • Variant expression and binding site proximity influence corrector sensitivity • Allosteric correction arises from binding energetics and vectorial stabilization McKee et al. utilize deep mutational scanning (DMS) to survey deviations in the plasma membrane expression (PME) of 129 clinical variants of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and how they respond to two FDA-approved cystic fibrosis (CF) drugs. This overview reveals factors associated with differences in the pharmacological properties of rare CF variants. [ABSTRACT FROM AUTHOR]

The article deals with some topical problems, and challenges of the time, dictating the need for modernization of the education system of Russia, shows the approaches to the reformation of existing pedagogical universities in European countries and presents the design approaches to the development of a pedagogical model division there in the context of reforming the Russian education system. The article is based on intermediate results of work of the project group in the framework of the strategic initiative "Teacher of the future" development Strategy of Nizhny Novgorod state pedagogical University named after Kozma Minin for the years 2014-2023. The article reveals the rationale for the development of the model of separation of pedagogical work in school and building on the basis of this model the corresponding system of teacher training in a pedagogical University. The basis for the design of a new system of learning based on the idea of the formation of meta-competences, which can ensure potential readiness of graduates of pedagogical universities to perform work in accordance with the concept of separation of pedagogical work.

A perfect mix of the air and fuel in internal combustion engines is desirable for proper combustion of fuel with air. The vehicles running on road emit harmful gases due to improper combustion. This problem is severe in heavy vehicles like locomotive engines. To overcome this problem, generally an operator opens or closes the valve of fuel injection pump of locomotive engines to control amount of air going inside the combustion chamber, which requires constant monitoring. A model is proposed in this paper to alleviate combustion process. The method involves recording the time-varying flow of fuel components in combustion chamber. A Fuzzy Neural Network is trained for around 40 fuels to ascertain the required amount of air to form a standard mix to produce non-harmful gases and about 12 fuels are used for testing the network’s performance. The network then adaptively determines the additional/subtractive amount of air required for proper combustion. Mean square error calculation ensures the effectiveness of the network’s performance.

To reduce cost, increase resolution, and reduce errors due to changing light intensity of the VIS SPEC, a new technique is proposed which applies the Kalman algorithm along with a simple hardware setup and implementation. In real time, the SPEC automatically corrects spectral data errors resulting from an unstable light source by adding a photodiode sensor to monitor the changes in light source intensity. The Kalman algorithm is applied on the data to correct the errors. The light intensity instability is one of the sources of error considered in this work. The change in light intensity is due to the remaining lifetime, working time and physical mechanism of the halogen lamp, and/or battery and regulator stability. Coefficients and parameters for the processing are determined from MATLAB simulations based on two real types of datasets, which are mono-changing and multi-changing datasets, collected from the prototype SPEC. From the saved datasets, and based on the Kalman algorithm and other computer algorithms such as divide-and-conquer algorithm and greedy technique, the simulation program implements the search for process noise covariance, the correction function and its correction coefficients. These components, which will be implemented in the processor of the SPEC, Kalman algorithm and the light-source-monitoring sensor are essential to build the Kalman corrector. Through experimental results, the corrector can reduce the total error in the spectra on the order of 10 times; for certain typical local spectral data, it can reduce the error by up to 60 times. The experimental results prove that accuracy of the SPEC increases considerably by using the proposed Kalman corrector in the case of changes in light source intensity. The proposed Kalman technique can be applied to other applications to correct the errors due to slow changes in certain system components.

Thanks to their high sensitivity and low-cost, metal oxide gas sensors (MOX) are widely used in gas detection, although they present well-known problems (lack of selectivity and environmental effects…). We present in this paper a novel neural network- based technique to remedy these problems. The idea is to create intelligent models; the first one, called corrector, can automatically linearize a sensor’s response characteristics and eliminate its dependency on the environmental parameters. The corrector’s responses are processed with the second intelligent model which has the role of discriminating exactly the detected gas (nature and concentration). The gas sensors used are industrial resistive kind (TGS8xx, by Figaro Engineering). The MATLAB environment is used during the design phase and optimization. The sensor models, the corrector, and the selective model were implemented and tested in the PSPICE simulator. The sensor model accurately expresses the nonlinear character of the response and the dependence on temperature and relative humidity in addition to their gas nature dependency. The corrector linearizes and compensates the sensor’s responses. The method discriminates qualitatively and quantitatively between seven gases. The advantage of the method is that it uses a small representative database so we can easily implement the model in an electrical simulator. This method can be extended to other sensors.

Background Mistrafficking of CFTR protein caused by F508del, the most frequent mutation in cystic fibrosis (CF), can be corrected by cell incubation at low temperature, an effect that may be mediated by altered expression of proteostasis genes. Methods To identify small molecules mimicking low temperature, we compared gene expression profiles of cells kept at 27 °C with those previously generated from more than 1300 compounds. The resulting candidates were tested with a functional assay on a bronchial epithelial cell line. Results We found that anti-inflammatory glucocorticoids, such as mometasone, budesonide, and fluticasone, increased mutant CFTR function. However, this activity was not confirmed in primary bronchial epithelial cells. Actually, glucocorticoids enhanced Na + absorption, an effect that could further impair mucociliary clearance in CF airways. Conclusions Our results suggest that rescue of F508del-CFTR by low temperature cannot be easily mimicked by small molecules and that compounds with closer transcriptional and functional effects need to be found. [ABSTRACT FROM AUTHOR]

The paper presents two organising solutions for vehicle trim correction realised with integrated shock absorber-air spring “ISAS” and their efficiency evaluation based simulation on complex quarter car models with ADAMS software – View module. ISAS is a new Romanian concept of shock absorber equipped with a metallic gas chamber convenient pressurized to realise the desired buoyant force. The main advantage of this new device is the high pressure it can work comparative to the known solutions realised with rubber sleeve/bellow, this giving possibility to fully eliminate the suspension steel spring. This ISAS advantage confer the possibility to modify vehicle trim, using classic solution with a trim corrector in parallel with the suspension steel spring or a solution, specific to the active suspension, with the trim corrector working singular, it assuring all buoyant force. The paper treats both two solutions based simulations on ¼ specific models and evaluates the results gave by both solutions in the same testing conditions. Both models are complex models equipped with nominated trim corrector and elastic stopper bumpers on both rebound and compression strokes. [ABSTRACT FROM AUTHOR]

Este estudio se propone investigar la validez y la Habilidad de la prueba de Inglés (PI) que se incluye en las Pruebas de Acceso a la Universidad (PAAU). 16 correctores participaron en las dos fases de este trabajo. En la primera fase, se analizaron las puntuaciones de 10 correctores que evaluaron 50 PI en las PAAU de la Universitat de les Illes Balears (UIB), junio de 2002. En la segunda fase, se examinaron las puntuaciones de 6 correctores que participaron en la corrección de las 50 PI de las PAAU en septiembre de 2002. Los resultados demuestran que la PI discrimina a los candidatos de acuerdo con su nivel de dominio lingüístico de la lengua. Los resultados también indican que la discriminación de los candidatos se establece principalmente a partir de las preguntas de carácter subjetivo que se incluyen en la Prueba. No obstante, la fiabilidad de dichas preguntas es cuestionable. Este último dato nos obliga a estudiar distintas medidas destinadas a garantizar la fiabilidad que esta prueba de dominio de le lengua inglesa debería tener.

We consider an elastic wave equation whose moduli depend on n separable microscopic scales and are periodic with respect to each scale in a domain D in R d . By using multiscale convergence, we deduce an ( n + 1 ) d dimensional problem that contains all the macroscopic and microscopic information on the multiscale equation. The full tensor product finite element approach is natural to solve this high dimensional multiscale homogenized equation but is too expensive practically. We develop a sparse tensor finite element approach that achieves essentially equal accuracy as the full tensor product finite elements but requires an essentially equal number of degrees of freedom as for solving a problem in R d . Restricting our consideration to the case of zero initial wave displacement, we deduce a corrector with a homogenization error estimate in the case of two scales. From this numerical correctors are constructed from the finite element solutions of the high dimensional multiscale homogenized problem with an error of the order of the sum of the homogenization and the finite element errors. For the general multiscale problems, we construct numerical correctors from the finite element solutions but without an explicit error. Numerical examples on two and three scale elastic wave equations in two dimensions confirm our analysis. [ABSTRACT FROM AUTHOR]

A perfect mix of the air and fuel in internal combustion engines is desirable for proper combustion of fuel with air. The vehicles running on road emit harmful gases due to improper combustion. This problem is severe in heavy vehicles like locomotive engines. To overcome this problem, generally an operator opens or closes the valve of fuel injection pump of locomotive engines to control amount of air going inside the combustion chamber, which requires constant monitoring. A model is proposed in this paper to alleviate combustion process. The method involves recording the time-varying flow of fuel components in combustion chamber. A Fuzzy Neural Network is trained for around 40 fuels to ascertain the required amount of air to form a standard mix to produce non-harmful gases and about 12 fuels are used for testing the network's performance. The network then adaptively determines the additional/subtractive amount of air required for proper combustion. Mean square error calculation ensures the effectiveness of the network's performance. [ABSTRACT FROM AUTHOR]

Abstract: The focus of this paper is on a thin obstacle problem where the obstacle is defined on the intersection between a hyper-plane in and a periodic perforation of , depending on a small parameter . As , it is crucial to estimate the frequency of intersections and to determine this number locally. This is done using strong tools from uniform distribution. By employing classical estimates for the discrepancy of sequences of type , , we are able to extract rather precise information about the set . As , we determine the limit of the solution to the obstacle problem in the perforated domain, in terms of a limit equation it solves. We obtain the typical “strange term” behavior for the limit problem, but with a different constant taking into account the contribution of all different intersections, that we call the averaged capacity. Our result depends on the normal direction of the plane, but holds for a.e. normal on the unit sphere in . [Copyright &y& Elsevier]

Background: Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods: To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R), the human ether-a-go-go-related gene (KCNH2, also known as hERG), and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1). We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p < 0.05). Results: Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions: Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases. [ABSTRACT FROM AUTHOR]

Over 100 mutations in the rhodopsin gene have been linked to a spectrum of retinopathies that include retinitis pigmentosa and congenital stationary night blindness. Though most of these variants exhibit a loss of function, the molecular defects caused by these underlying mutations vary considerably. In this work, we utilize deep mutational scanning to quantitatively compare the plasma membrane expression of 123 known pathogenic rhodopsin variants in the presence and absence of the stabilizing cofactor 9-cis-retinal. We identify 69 retinopathy variants, including 20 previously uncharacterized variants, that exhibit diminished plasma membrane expression in HEK293T cells. Of these apparent class II variants, 67 exhibit a measurable increase in expression in the presence of 9-cis-retinal. However, the magnitude of the response to this molecule varies considerably across this spectrum of mutations. Evaluation of the observed shifts relative to thermodynamic estimates for the coupling between binding and folding suggests underlying differences in stability constrains the magnitude of their response to retinal. Nevertheless, estimates from computational modeling suggest that many of the least sensitive variants also directly compromise binding. Finally, we evaluate the functional properties of three previous uncharacterized, retinal-sensitive variants (ΔN73, S131P, and R135G) and show that two of these retain residual function in vitro. Together, our results provide a comprehensive experimental characterization of the proteostatic properties of retinopathy variants and their response to retinal., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Cystic fibrosis (CF) is a genetic disease that is difficult to treat and caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have been used to treat the symptom caused by CFTR mutations by restoring CFTR protein function. However, the data on children with CF are scarce. This meta-analysis aimed to evaluate the effectiveness and safety of this therapy in children diagnosed with CF., Materials and Methods: Relevant studies were identified through searching medical databases before April 1, 2022. The primary outcomes of ppFEV 1 , lung clearance index 2.5 (LCI 2.5 ), sweat chloride concentration (SwCI), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were nutritional status (weight, BMI, stature, and their z-score) and adverse events under therapy., Results: A total of twelve studies were included. Compared with the placebo group, the pooled outcome of the ppFEV1, LCI 2.5 , SwCI, and CFQ-R score were improved by 7.91 {[95% confidence interval (CI), 3.71-12.12], -1.00 (95% CI, -1.38 to -0.63), -35.22 (95% CI, -55.51 to -14.92), and 4.45 (95% CI, 2.31-6.59), respectively}. Compared with the placebo group, the pooled result of the change in weight was improved by 1.53 (95% CI, 0.42-2.63). All the aforementioned results were also improved in single-arm studies. No clear differences in adverse events were found between CFTR modulator therapy and the placebo group., Conclusion: CFTR modulators could improve multiaspect function in children with CF and result in comparable adverse events., 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 Li, Liu, Ma and Yu.)

Abstract: We construct harmonic functions on random graphs given by Delaunay triangulations of ergodic point processes as the limit of the zero-temperature harness process. [Copyright &y& Elsevier]

Abstract: In this paper, we develop a viscosity method for homogenization of Nonlinear Parabolic Equations constrained by highly oscillating obstacles or Dirichlet data in perforated domains. The Dirichlet data on the perforated domain can be considered as a constraint or an obstacle. Homogenization of nonlinear eigen value problems has been also considered to control the degeneracy of the porous medium equation in perforated domains. For the simplicity, we consider obstacles that consist of cylindrical columns distributed periodically and perforated domains with punctured balls. If the decay rate of the capacity of columns or the capacity of punctured ball is too high or too small, the limit of will converge to trivial solutions. The critical decay rates of having nontrivial solution are obtained with the construction of barriers. We also show the limit of satisfies a homogenized equation with a term showing the effect of the highly oscillating obstacles or perforated domain in viscosity sense. [Copyright &y& Elsevier]

Cystic fibrosis (CF) is a lethal recessive genetic disease caused by mutations in the CFTR gene. The gene product is a PKA-regulated anion channel that is important for fluid and electrolyte transport in the epithelia of lung, gut, and ducts of the pancreas and sweat glands. The most common CFTR mutation, ΔF508, causes a severe, but correctable, folding defect and gating abnormality, resulting in negligible CFTR function and disease. There are also a large number of rare CF-related mutations where disease is caused by CFTR misfolding. Yet the extent to which defective biogenesis of these CFTR mutants can be corrected is not clear. CFTRV232D is one such mutant that exhibits defective folding and trafficking. CFTRΔF508 misfolding is difficult to correct, but defective biogenesis of CFTRV232D is corrected to near wild-type levels by small-molecule folding correctors in development as CF therapeutics. To determine if CFTRV232D protein is competent as a Cl- channel, we utilized single-channel recordings from transfected human embryonic kidney (HEK-293) cells. After PKA stimulation, CFTRV232D channels were detected in patches with a unitary Cl- conductance indistinguishable from that of CFTR. Yet the frequency of detecting CFTRV232D channels was reduced to ∼20% of patches compared with 60% for CFTR. The folding corrector Corr-4a increased the CFTRV232D channel detection rate and activity to levels similar to CFTR. CFTRV232D-corrected channels were inhibited with CFTRinh-172 and stimulated fourfold by the CFTR channel potentiator VRT-532. These data suggest that CF patients with rare mutations that cause CFTR misfolding, such as CFTRV232D, may benefit from treatment with folding correctors and channel potentiators in development to restore CFTR?F508 function. [ABSTRACT FROM AUTHOR]