Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF

Self-dual noncommutative \phi^4-theory in four dimensions is a non-perturbatively solvable and non-trivial quantum field theory

We study quartic matrix models with partition function Z[E,J]=\int dM \exp(trace(JM-EM^2-(\lambda/4)M^4)). The integral is over the space of Hermitean NxN-matrices, the external matrix E encodes the dynamics, \lambda>0 is a scalar coupling constant and the matrix J is used to generate correlation functions. For E not a multiple of the identity matrix, we prove a universal algebraic recursion formula which gives all higher correlation functions in terms of the 2-point function and the distinct eigenvalues of E. The 2-point function itself satisfies a closed non-linear equation which must be solved case by case for given E. These results imply that if the 2-point function of a quartic matrix model is renormalisable by mass and wavefunction renormalisation, then the entire model is renormalisable and has vanishing \beta-function. As main application we prove that Euclidean \phi^4-quantum field theory on four-dimensional Moyal space with harmonic propagation, taken at its self-duality point and in the infinite volume limit, is exactly solvable and non-trivial. This model is a quartic matrix model, where E has for N->\infty the same spectrum as the Laplace operator in 4 dimensions. Using the theory of singular integral equations of Carleman type we compute (for N->\infty and after renormalisation of E,\lambda) the free energy density (1/volume)\log(Z[E,J]/Z[E,0]) exactly in terms of the solution of a non-linear integral equation. Existence of a solution is proved via the Schauder fixed point theorem. The derivation of the non-linear integral equation relies on an assumption which we verified numerically for coupling constants 0<\lambda\leq (1/\pi).Comment: LaTeX, 64 pages, xypic figures. v4: We prove that recursion formulae and vanishing of \beta-function hold for general quartic matrix models. v3: We add the existence proof for a solution of the non-linear integral equation. A rescaling of matrix indices was necessary. v2: We provide Schwinger-Dyson equations for all correlation functions and prove an algebraic recursion formula for their solutio

THEORETICAL RESEARCH REGARDING THE WORKING PROCESS OF THE FERTILIZERS MANAGING SYSTEMS BY CENTRIFUGATION

Achieving a distribution standards per hectare as uniform and as specified by eachculture is the most important objective when it comes to administering fertilizer machine. In this sense the paper aims to highlight the theoretical and experimental research conducted by specialists from home and abroad on the process of working machines administrator chemical fertilizer granulation, according to parameters that can influence this process: as blades, the angle of their and so on

From CFTR biology toward combinatorial pharmacotherapy:expanded classification of cystic fibrosis mutations

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients

Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell

Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (Delta F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 degrees C and concomitant functional inactivation of Delta F508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at singlemolecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart. Thus, molecular chaperones can contribute to functional maintenance of Delta F508-CFTR by reshaping the conformational energetics of its final fold, a mechanism with implication in the regulation of metastable ABC transporters and other plasma membrane proteins activity in health and diseases

Mind the Gap: Transitions Between Concepts of Information in Varied Domains

The concept of 'information' in five different realms – technological, physical, biological, social and philosophical – is briefly examined. The 'gaps' between these conceptions are dis‐ cussed, and unifying frameworks of diverse nature, including those of Shannon/Wiener, Landauer, Stonier, Bates and Floridi, are examined. The value of attempting to bridge the gaps, while avoiding shallow analogies, is explained. With information physics gaining general acceptance, and biology gaining the status of an information science, it seems rational to look for links, relationships, analogies and even helpful metaphors between them and the library/information sciences. Prospects for doing so, involving concepts of complexity and emergence, are suggested