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

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

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

DECOVID:A UK Two-Center Harmonized Database of Acute Care Electronic Health Records for COVID-19 Research

The DECOVID database contains harmonized pseudonymized electronic health record (EHR) data on all adult (≥18 years old) patients presenting to two large, digitally mature centers in the United Kingdom between 1 January 2020 and 28 February 2021, with follow-up until at least 28 March 2021. The database was originally developed to support the COVID-19 response but is now available via the PIONEER data hub for researchers to explore a wide range of research questions, including exploratory analyses, risk factor assessment, prediction modeling, and comparative effectiveness studies. Raw data were extracted from local EHRs and transformed into a standardized form (Observational Health Data Sciences and Informatics-Common Data Model version 5.3.1). The database includes 165,420 patients across 256,804 hospital presentations. For these patients, highly granular data are available, including patient demographics, longitudinal vital signs, physiology, treatments, laboratory findings, clinical diagnoses, and outcomes. There are 10,030 patients with COVID-19, of whom 1472 died in hospital

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