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We consider second-order parabolic equations with bounded measurable ε-periodic coefficients. To solve the Cauchy problem in the layer ℝd × (0, T) with the nonhomogeneous equation, we obtain approximations in the norm ‖ ∙ ‖ L 2 R d × 0 , T with remainder of order ε2 as ε → 0. [ABSTRACT FROM AUTHOR]

In this paper we investigate the 2d-model for a thin plate Ω ε : = ω × ε I of R 3 having two components: a circular stiff layer F ε and its complement the soft matrix M ε with 1 ε 2 as a ratio between their respective elasticity coefficients. We prove that the limit model is associated to a nonlocal system involving Kirchoff-Love displacements in the layer and we exhibit a corrector for the displacements in the initial cylindrical structure of R 3 . [ABSTRACT FROM AUTHOR]

For a homogenization problem associated to a linear elliptic operator, we prove the existence of a distributional corrector and we find an approximation scheme for the homogenized coefficients. We also study the convergence rates in the asymptotic almost periodic setting, and we show that the rates of convergence for the zero-order approximation, are near optimal. The results obtained constitute a step towards the numerical implementation of results from the deterministic homogenization theory beyond the periodic setting. To illustrate this, numerical simulations based on finite volume method are provided to sustain our theoretical results. [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.

• Expression and pharmacological rescue of G1244E-CFTR depend on cell background. • In heterologous models elexacaftor mainly acts on G1244E-CFTR as a co-potentiator. • In native cells, elexacaftor increases mature CFTR expression. • Co-potentiators are needed to improve channel activity of G1244E-CFTR. • Development of novel co-potentiating drugs will help rescue of G1244E-CFTR. Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator. By using molecular, biochemical and functional analyses we performed an in-depth characterization of the G1244E-CFTR mutant in heterologous and native cell models. Our studies demonstrate that processing and function of the mutant protein, as well as its pharmacological sensitivity, are markedly dependent on cell background. In heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator, thus ameliorating the gating defect. On the contrary, in the native nasal epithelial cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR expression possibly by improving mutant's defective stability at the plasma membrane. Our study highlights the importance of the cell background in the evaluation of CFTR modulator effects. Further, our results draw attention to the need for the development of novel potentiators having different mechanisms with respect to ivacaftor to improve channel activity for mutants with severe gating defect. [ABSTRACT FROM AUTHOR]

The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution three-dimensional (3D) structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators. [ABSTRACT FROM AUTHOR]

Let Ω be a Lipschitz domain in Rd, and let Aε=-divA(x,x/ε)∇ be a strongly elliptic operator on Ω. We suppose that ε is small and the function A is Hölder continuous of order s∈(0,1] in the first variable and periodic in the second, so the coefficients of Aε are locally periodic and rapidly oscillate. Given μ in the resolvent set, we are interested in finding the rates of approximations, as ε→0, for (Aε-μ)-1 and ∇(Aε-μ)-1 in the operator topology on Lp for suitable p. It is well-known that the rates depend on regularity of the effective operator A0. We prove that if (A0-μ)-1 and its adjoint are bounded from Lp(Ω)n to the Lipschitz-Besov space Λ1+sp(Ω)n with the same s as for A, then the rates are, respectively, εs and εs/p. The results are applied to the Dirichlet, Neumann, and mixed Dirichlet-Neumann problems for strongly elliptic operators with uniformly bounded and vanishing mean oscillation coefficients. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the one‐dimensional model for a thin three‐dimensional structure Ω^ε$$ {\hat{\Omega}}_{\varepsilon } $$ in the framework of the thermal conduction. The structure is characterized by two small positive parameters ε$$ \varepsilon $$ and rε$$ {r}_{\varepsilon } $$. The first parameter ε$$ \varepsilon $$ corresponds to the thickness of the structure while the second one characterizes the thickness of its core Tε$$ {T}_{\varepsilon } $$ which plays the role of a "hole." The structure is assumed to be heterogeneous and anisotropic, and we deal with three cases related to the limit limε→0ε2|ln(rε)|=k,k∈{0,1,+∞}$$ \underset{\varepsilon \to 0}{\lim}\kern.3em {\varepsilon}^2\mid \ln \left({r}_{\varepsilon}\right)\mid =k,k\in \left\{0,1,+\infty \right\} $$. We exhibit the "strange" term appearing in the one‐dimensional model in the critical case k=1$$ k=1 $$, and we highlight the effect of the anisotropy on the form of the corrector for uε$$ {u}_{\varepsilon } $$. [ABSTRACT FROM AUTHOR]

We consider resolvents (A ϵ + 1) − 1 of elliptic second-order differential operators A ϵ = − div a (x / ϵ) ∇ in R d with ε-periodic measurable matrix a (x / ϵ) and study the asymptotic behaviour of (A ϵ + 1) − 1 , as the period ε goes to zero. We provide a construction for the leading terms of the 'operator asymptotics' of (A ϵ + 1) − 1 in the sense of L 2 -operator-norm convergence and prove order ϵ 2 remainder estimates. We apply the modified method of the first approximation with the usage of Steklov's smoothing. The class of operators covered by our analysis includes uniformly elliptic families with bounded coefficients and also with unbounded coefficients from the John–Nirenberg space BMO (bounded mean oscillation). [ABSTRACT FROM AUTHOR]

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.

We consider the homogenization of a non-linear elliptic system of two equations related to some models in chemotaxis and flows in porous media. One of the equations contains a convection term where the transport vector is only in L 2 and a right-hand side which is only in L 1 . This makes it necessary to deal with entropy or renormalized solutions. The existence of solutions for this system has been proved in reference (Comm. Partial Differential Equations45(7) (2020) 690–713). Here, we prove its stability by homogenization and that the correctors corresponding to the linear diffusion terms still provide a corrector for the solutions of the non-linear system. [ABSTRACT FROM AUTHOR]

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]

This paper is devoted to the study of the error estimates in the periodic homogenization of elliptic equations in divergence form with Dirichlet boundary conditions. We are interested in the application of a two-scale asymptotic expansions method. We present the error estimates of the third-order with and without boundary layers terms. [ABSTRACT FROM AUTHOR]

In this paper, we consider the problem of constructing a correction algorithm with the aim of increasing the adaptive properties of the ΣΠ-neuron, relying solely on the structure of the ΣΠ-neuron itself. To build the corrector, the logical-algebraic method of data analysis is used. Comparison of the advantages of the neural network approach and the logical-algebraic method suggests that a combined approach to the organization of the neural network improves its efficiency and allows one to build a set of rules that reveal hidden patterns in a given subject area, thus improving the quality of the recognition system. [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.

An elliptic fourth-order differential operator on is studied. Here is a small parameter. It is assumed that the operator is given in the factorized form , where is a Hermitian matrix-valued function periodic with respect to some lattice and is a matrix second-order differential operator. We make assumptions ensuring that the operator is strongly elliptic. The following approximation for the resolvent in the operator norm of is obtained: Here is the effective operator with constant coefficients and and are certain correctors. [ABSTRACT FROM AUTHOR]

We study the ergodic theory of stationary directed nearest-neighbor polymer models on Z 2 , with i.i.d. weights. Such models are equivalent to specifying a stationary distribution on the space of weights and correctors that satisfy certain consistency conditions. We show that for a prescribed weight distribution and corrector mean, there is at most one stationary polymer distribution which is ergodic under the e 1 or e 2 shift. Further, if the weights have more than two moments and the corrector mean vector is an extreme point of the superdifferential of the limiting free energy, then the corrector distribution is ergodic under each of the e 1 and e 2 shifts. [ABSTRACT FROM AUTHOR]

Since the cloning of the CFTR gene 30 years ago, research aiming at understanding how CFTR mutations translate to abnormal synthesis or function of the CFTR protein has opened the way to genomically-guided therapy to improve CFTR function. A CFTR potentiator to enhance CFTR channel function has been approved in 2012 for specific and quite rare mutations. Subsequently, combinations of a corrector to increase CFTR expression at the cell membrane, plus a potentiator, have been approved for patients homozygous for the p.Phe508del mutation. To obtain robust correction of CFTR, new combinations of drugs are being studied. A triple combination associating two correctors and one potentiator is very promising and if data of clinical trials are confirmed, it could be a robust and well tolerated CFTR modulator for patients bearing at least one p.Phe508del mutation. Many other strategies are also in development to make these genomically-guided treatments available to all patients with CF. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved. [ABSTRACT FROM AUTHOR]

As the nineteenth book of his Decretum, Bishop Burchard of Worms (d. 1025) included a penitential titled the Corrector or Medicus. Although the Corrector has traditionally been described as a manual of private confession, this article argues that it was primarily used to judge public penances at church courts and synods. Focusing on the manuscript transmission of the Decretum in the eleventh and twelfth centuries, we find that the Corrector was almost never copied apart from the rest of the Decretum and that it was almost always copied alongside other legal texts. Turning to individual abbreviations, we also find that Burchard's collection was frequently reworked and rearranged so as to integrate canonical and penitential texts. These findings call into question current definitions of canon law collections and penitentials which presume functional exclusivity. [ABSTRACT FROM AUTHOR]

The paper is divided in two parts. In the first one, we consider a linear elliptic partial differential equation, or system, in an unbounded cylinder with a nonpositive term of zero order. We analyze the existence and the dimension of the space of solutions, when we look for solutions which tend exponentially to zero at infinity and for oscillatory solutions which have a potential growth at infinity. This type of problems appears when we study the influence of boundary conditions in homogenization, singular perturbation problems and reduction of dimension problems. As an example, we obtain a corrector result for a wave problem in a thin beam imposing initial and boundary conditions. It was known that the initial conditions produce almost periodic oscillations in time. Here, we show that the boundary conditions also produce almost periodic oscillations in the direction of the axis of the beam. [ABSTRACT FROM AUTHOR]

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]

Abstract Cystic fibrosis (CF) is a life-limiting genetic disease that arises from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and protein. This causes abnormal epithelial ion transport. CF is a multisystem condition but airway infection and inflammation carry the greatest treatment burden and are the predominant cause of morbidity and mortality. Novel therapeutic strategies have recently been developed to target specific molecular defects arising from CFTR mutations. These CFTR modulator therapies are designed to correct the underlying protein processing defect or to potentiate CFTR function to improve ion transport. Such advances have revolutionized CF treatment approaches, which have previously only addressed downstream effects, and hold significant promise for the future. This review will summarize recent advances in CFTR modulator development and how these have impacted upon treatment outcomes and the lives of people with CF. [ABSTRACT FROM AUTHOR]

The 1,2,3‐triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX‐809 and VX‐770, prominent amide‐containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX‐809, displayed markedly reduced efficacy in F508del‐CFTR correction in cellular TECC assays in comparison to VX‐809. Surprisingly, triazole analogues derived from potentiator VX‐770 displayed no potentiation of F508del, G551D, or WT‐CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT‐CFTR similarly to VX‐770. The efficacy of 60 in the cell‐free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX‐770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3‐triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3‐triazole as an amide bioisostere. Trying out the triazole as an amide bioisostere in CFTR modulators VX‐809 and VX‐770 revealed that triazole derivatives of VX‐809 and VX‐770 displayed significantly decreased efficacy or inactivity in cellular assays. In addition, triazole derivatives displayed decreased metabolic stability in hepatic microsomal assays. These findings represent an important counterpoint to the many successful uses of the triazole as an amide bioisostere. [ABSTRACT FROM AUTHOR]

We establish viscosity vanishing limit of the nonlinear pipe magnetohydrodynamic flow by the mathematical validity of the Prandtl boundary layer theory with fixed diffusion. The convergence is verified under various Sobolev norms, including the L∞(H1) norm. [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 complete a well-balanced numerical method by introducing computing correctors to an earlier scheme for a model of two-phase flows. Each improvement based on a corrector to the scheme is designed to reduce the size of the errors across the interface of each node when using the solid contact to absorb the nonconservative terms. Three correctors of two kinds are presented. One corrector of the first kind is designed to correct the states on both side of the solid contact at each node and the corresponding numerical flux before applying the iterative scheme. Two correctors of the second kind are designed to correct the state given by the iterative scheme depending on the sign of the velocity of the solid contact. These improvements are still well-balanced schemes. Tests show that the improvement by using the corrector of the first kind gives relatively better results, and the improvements by using one corrector of the second kind give much better results. Interestingly, we find that improvements by using a corrector of second kind can resolve the accuracy problem of the existing scheme when its approximate solutions might converge to the solution slightly different from the exact solution. [ABSTRACT FROM AUTHOR]

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]

The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity. [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]